| disease | Cold-damage Disease |
| alias | Enteric Fever, Typhoid Fever, Enteric Fever |
Cold-damage disease (typhoid fever) is an acute pestilence caused by the cold-damage disease bacillus, characterized by persistent bacteremia, involvement of the reticuloendothelial system, microscopic abscesses in the distal ileum, and ulcer formation as its fundamental pathological features. Typical clinical manifestations include persistent high fever, abdominal discomfort, hepatosplenomegaly, leukopenia, and in some patients, rose spots and a relatively moderate pulse. This disease is also known as enteric Rebing (enteric fever). However, the clinical manifestations primarily result from the dissemination of the pathogen through the bloodstream to various organs throughout the body, rather than being caused by localized intestinal lesions.
bubble_chart Epidemiology
(1) Source of pestilence: Patients and carriers are the sources. Patients can excrete bacteria in feces starting from the incubation period and in urine from the end of the first week of the illness. Therefore, they remain pestilent throughout the course of the disease, especially during weeks 2 to 4, when pestilence is at its peak.
Chronic carriers are mostly found in the gallbladder and bile ducts, primarily among women over 40 years old; urinary tract carriers are rare. Patients with pre-existing chronic hepatobiliary diseases (such as cholecystitis, cholelithiasis, or clonorchiasis) or urinary tract diseases (such as pyelonephritis, bladder inflammation) are more likely to become chronic carriers.
(2) Transmission route: Cold-damage disease bacilli are excreted in the feces or urine of patients or carriers and spread through contaminated water, food, daily contact, and vectors such as flies and cockroaches.
(3) Population susceptibility: Humans are generally susceptible to cold-damage disease. After infection, lasting immunity is acquired, and reinfection is extremely rare.(4) Epidemiological characteristics: The disease occurs year-round but is most prevalent in summer and autumn. The peak incidence in northern regions usually occurs 1–2 months later than in southern regions. In recent years, the incidence rate has decreased across China, and the epidemic peak has flattened. The disease predominantly affects children and young adults, with 20–40-year-olds accounting for about 60–80% of adult cases, while those over 40–50 years old are less commonly affected. Recently, there has been a relative increase in cases among children and infants, with those under 15 years old making up 35–60% of total cases.
The pathogen of this disease is the cold-damage disease bacillus, which belongs to group D of the Salmonella genus. It is Gram-negative, short rod-shaped, measuring 1–3.5 μm in length and 0.5–0.8 μm in width, with peritrichous flagella that enable motility. It does not produce spores and lacks a capsule. It can grow on ordinary culture media but thrives better on media containing bile.
The cold-damage disease bacillus exhibits strong viability in nature. It can generally survive in water for 2–3 weeks, persist in feces for 1–2 months, and not only survive but also multiply in milk. It is resistant to low temperatures, enduring for several months in freezing conditions. However, it is relatively weak against light, heat, drying, and disinfectants. Direct sunlight kills it within a few hours, heating to 60°C for 30 minutes or boiling causes immediate death, and it is killed within 5 minutes in 3% phenol. A residual chlorine level of 0.2–0.4 mg/L in disinfected drinking water can rapidly kill it.
The cold-damage disease bacillus infects only humans and does not infect animals under natural conditions. Upon lysis, this bacterium releases a potent internal toxin, which plays a significant role in the onset and progression of the disease. Injecting a small amount of internal toxin into humans or rabbits intravenously can induce shivering, fever, malaise, and leukopenia—symptoms highly similar to those of cold-damage disease patients. The somatic ("O") antigen, flagellar ("H") antigen, and surface ("Vi") antigen of the cold-damage disease bacillus can all produce corresponding antibodies, but these are not protective antibodies. Due to the strong antigenicity of the "O" and "H" antigens, they are commonly used in serological agglutination tests (Widal reaction) to aid clinical diagnosis and can also be used to prepare cold-damage disease vaccines for immunization. The "Vi" antigen is found in newly isolated strains (particularly those isolated from patient blood) and can interfere with the bactericidal and phagocytic functions in serum, serving as a key factor in determining the virulence of the cold-damage disease bacillus. However, its antigenicity is weak, and the agglutination titer of the resulting "Vi" antibodies is generally low and short-lived. Once the pathogen is cleared from the body, the "Vi" antibody titer rapidly declines. Although detecting "Vi" antibodies is not particularly helpful for diagnosing the disease, it aids in identifying carriers. Cold-damage disease bacilli containing the "Vi" antigen can be lysed by specific bacteriophages. Using "Vi" type II bacteriophages, the cold-damage disease bacillus can be classified into approximately 100 phage types, which assists in tracking the source of epidemics. bubble_chart Pathogenesiscold-damage disease bacilli enter the digestive tract through contaminated water or food and are usually killed by stomach acid. However, if the invading pathogens are numerous or gastric acid is lacking, the pathogenic bacteria can reach the small intestine and invade the intestinal mucosa. At this stage, some bacteria are engulfed by macrophages and multiply within their cytoplasm, while others enter the lymphatic vessels and proliferate in the ileal Peyer's patches, solitary lymphatic follicles, and mesenteric lymph nodes. Subsequently, they enter the bloodstream via the thoracic duct, causing a transient bacteremia known as the primary bacteremic phase. During this stage, patients show no symptoms, corresponding to the clinical incubation period.
cold-damage disease bacilli enter the liver, spleen, gallbladder, kidneys, and bone marrow via the bloodstream, where they multiply extensively before re-entering the bloodstream, causing a second severe bacteremia and releasing potent internal toxins. This leads to clinical symptoms such as fever, general malaise, rose spots on the skin, and hepatosplenomegaly. This phase corresponds to weeks 1–2 of the disease course, during which toxemia symptoms gradually worsen. Blood cultures are often positive, and the highest concentration of cold-damage disease bacilli is found in the bone marrow, where they persist the longest, resulting in the highest culture positivity rate. During weeks 2–3 of the disease course, cold-damage disease bacilli continue to disseminate throughout the body via the bloodstream, reaching various organs and the skin. They enter the intestinal tract via the bile ducts and are excreted in feces, while others are excreted in urine via the kidneys. At this stage, stool and urine cultures may yield positive results. Some bacilli that re-enter the intestinal tract via the bile ducts penetrate the small intestine mucosa again and invade the intestinal lymphoid tissue, triggering a severe inflammatory response and mononuclear cell infiltration in the already sensitized tissue. This leads to necrosis, sloughing, and ulcer formation. If the blood vessels in the affected area are involved, hemorrhage may occur, while penetration of the muscle and serosal layers can result in intestinal perforation. Additionally, cold-damage disease bacilli can cause suppurative inflammation in other tissues, such as osteomyelitis, renal abscesses, cholecystitis, meningitis, and pericarditis.
By the fourth week of the disease course, the body's immune response gradually strengthens, manifesting as enhanced humoral and cellular immunity and increased phagocytic activity. Cold-damage disease bacilli gradually disappear from the bloodstream and organs, and intestinal ulcers begin to heal, leading to eventual recovery. In a small number of cases, due to insufficient immune function or other factors, latent cold-damage disease bacilli may proliferate again and re-enter the bloodstream, causing relapse.
bubble_chart Pathological Changes
The main pathological feature of cold-damage disease is the proliferative reaction of large mononuclear cells (macrophages) in the systemic reticuloendothelial system, with the intestines being the most prominent. During days 7–10 of the disease course, the intestinal lymphoid tissue proliferates and swells, forming button-like protrusions, particularly in the aggregated and solitary lymph nodes at the distal end of the ileum. A few cases also show similar changes in the initial segment of the colon. The mesenteric lymph nodes also exhibit significant hyperplasia and enlargement. Lymph nodes in other areas, the spleen, bone marrow, and hepatic sinusoidal stellate cells also show hyperplasia. Subsequently, the lesions in the intestinal lymphoid tissue worsen, leading to local nutritional disturbances and necrosis, forming yellow scabs. By the third week of the disease course, the scabs slough off, forming ulcers. If the lesions involve blood vessels, hemorrhage may occur; if they invade the muscular layer and serosa, intestinal perforation may result. Since the lymph nodes at the distal end of the ileum are larger and more numerous, the lesions are most severe here, making perforation more common in this area. The ulcers are often oval or round, arranged along the longitudinal axis of the intestine, with surrounding intestinal mucosa showing congestion. By weeks 4–5 of the disease course, the ulcers heal without scarring or causing intestinal strictures. The intestinal lesions do not necessarily correlate with the severity of clinical symptoms. Patients with severe toxemia, especially infants, may have inconspicuous intestinal lesions, whereas those with mild or absent toxemia may suddenly experience intestinal hemorrhage or perforation.
Microscopic examination reveals that the prominent feature of these lesions is the infiltration of inflammatory cells dominated by macrophages, with no neutrophils. These macrophages are abundant at the base and periphery of small intestine ulcers and exhibit strong phagocytic activity. Their cytoplasm contains engulfed lymphocytes, red blood cells, cold-damage disease bacilli, and necrotic tissue debris, which are relatively characteristic pathological changes of this disease. Hence, they are referred to as "cold-damage disease cells." If these cells aggregate into clusters, they are termed cold-damage disease granulomas or cold-damage disease nodules.
Among other organs, the spleen and liver exhibit the most significant lesions. The spleen is enlarged, often weighing over 500g, with congestion, hyperplasia of reticuloendothelial cells, and the formation of cold-damage disease granulomas. The most common liver lesion is focal necrosis of hepatocytes accompanied by mononuclear cell infiltration. Some consider this lesion a "nonspecific reactive hepatitis," which can also be seen in patients with ulcerative colitis, regional enteritis, and intestinal amoebiasis.
The gallbladder may show grade I inflammation, with acute inflammation being rare. The myocardium and kidneys appear cloudy, a manifestation of toxemia. Endocarditis and pericarditis are extremely rare. Thrombophlebitis occasionally occurs, mostly in the left femoral vein. Cystitis and pyelitis are uncommon. Orchitis is rare. Osteomyelitis (often in the tibia) and spondylitis may occasionally occur. The nervous system shows no specific lesions, and cold-damage disease bacillus meningitis is only rarely seen. In the respiratory system, bronchitis is common, but secondary bronchopneumonia and lobar pneumonia may also occur. Microscopic examination of the maculopapular rash (rose spots) reveals mononuclear cell infiltration and capillary dilation, with cold-damage disease bacilli occasionally observed.
bubble_chart Clinical Manifestations
The incubation period is about 10 days, and its duration is related to the amount of bacteria infected. Food-borne outbreaks can be as short as 48 hours, while water-borne outbreaks can last up to 30 days.
Typical cold-damage disease
The natural course of typical cold-damage disease lasts about 4 weeks and can be divided into 4 stages:
(1) Initial stage [first stage] Corresponding to the first week of the course, the onset is mostly gradual (75–90%). Fever is the earliest symptom, often accompanied by general malaise, lack of strength, loss of appetite, sore throat, and cough. The condition gradually worsens, with body temperature rising in a step-like manner, reaching 39–40°C within 5–7 days. Before the fever, there may be fear of cold but little shivering, and sweating is not significant when the fever subsides.
(2) Peak stage Corresponding to the second to third week of the course, it often presents with the typical manifestations of cold-damage disease, which aids in diagnosis.
1. High fever The high fever persists, with most cases (50–75%) showing a sustained fever pattern, while a few show a remittent or irregular fever pattern, lasting about 10–14 days.
2. Digestive symptoms Loss of appetite becomes more pronounced, the tip and edges of the tongue are red, with a thick and greasy coating (the so-called cold-damage disease tongue). There may be abdominal discomfort, abdominal distension and fullness, mostly constipation, and a few cases mainly present with diarrhea. Since intestinal lesions mostly occur in the terminal ileum and ileocecal region, there may be grade I tenderness in the right lower abdomen.
3. Neurological symptoms These are proportional to the severity of the disease and are caused by the effect of cold-damage disease bacillus endotoxin on the central nervous system. Patients may appear dazed, indifferent, sluggish, and slow to react, with impaired hearing. In severe cases, delirium, unconsciousness, or signs of meningeal irritation (false meningitis) may occur. These neurological symptoms usually gradually improve as body temperature decreases.
4. Circulatory symptoms A relative moderate pulse (20–73%) or occasionally a dicrotic pulse is one of the clinical features of this disease. However, in cases complicated by toxic myocarditis, the relative moderate pulse is less obvious.
5. Splenomegaly Starting from the sixth day of the course, splenomegaly (60–80%) can often be palpated in the left hypochondrium, with a soft texture and possible tenderness. A few patients may also have hepatomegaly (30–40%), with a soft texture and possible tenderness. Severe cases may present with jaundice, and significant liver function abnormalities suggest the presence of toxic hepatitis.
6. Rash On days 7–13 of the course, some patients (20–40%) may develop small, pale red maculopapules (rose spots) on the skin, about 2–4 mm in diameter, which fade upon pressure. There are usually fewer than 12 spots, appearing in batches, mainly distributed on the chest and abdomen, but also seen on the back and limbs, disappearing within 2–4 days. Miliaria crystallina (or white prickly heat) is also common, often occurring in those who sweat more.
(3) Stage of remission Corresponding to the third to fourth week of the course, the body's resistance to cold-damage disease bacillus gradually increases, body temperature fluctuates and begins to decline, appetite gradually improves, and abdominal distension and fullness gradually disappear. The spleen begins to shrink. However, there is a risk of intestinal hemorrhage or perforation during this stage, requiring special vigilance.
(4) Stage of convalescence Corresponding to the end of the fourth week of the course. Body temperature returns to normal, appetite improves, and full recovery is usually achieved within about 1 month.
Other clinical types
In addition to the typical cold-damage disease described above, depending on factors such as the patient's age, immune status, the virulence and quantity of the pathogen, irregular use of antibiotics in the initial stage [first stage], and the presence of complications, cold-damage disease can also be classified into the following types.
(1) Mild type Systemic toxic symptoms are mild, and the course is short, with recovery within 1–2 weeks. This is commonly seen in patients who have received cold-damage disease vaccination before onset or those treated with effective antibiotics in the initial stage [first stage]. It is also not uncommon in pediatric cases. Due to the mild condition and atypical symptoms, misdiagnosis or missed diagnosis is likely.
(2) Fulminant type The onset is acute, with severe toxic symptoms, including fear of cold, high fever, abdominal pain, diarrhea, toxic encephalopathy, myocarditis, hepatitis, intestinal paralysis, shock, etc. There are often significant rashes, and DIC may also occur.
(3) Protracted Type The onset is similar to that of typical cold-damage disease. Due to compromised immune function, the fever persists without abating and can last for 45 to 60 days. Patients with cold-damage disease accompanied by chronic schistosomiasis often fall into this category.
When cold-damage disease is complicated by schistosomiasis, the onset is often acute, fever is usually remittent or intermittent, hepatosplenomegaly is more pronounced, eosinophils are significantly reduced or absent during the fever phase and the critical period, and they rebound after the fever subsides, often exceeding normal values. The febrile course may persist for 1–2 months.
(4) Pediatric cold-damage disease Generally, the older the child, the more the clinical manifestations resemble those of adults, while the younger the child, the more atypical the symptoms.
School-aged children exhibit symptoms similar to adults, but most cases are mild. The onset is often acute, with persistent fever, loss of appetite, abdominal pain, constipation, apathy, drowsiness, dysphoria, epistaxis, thick tongue coating, abdominal distension and fullness, and hepatosplenomegaly. However, moderate pulse and rose spots are rare, and the white blood cell count is often not reduced. The course of the disease is shorter, sometimes resolving naturally in just 2–3 weeks. Due to mild intestinal lesions, complications such as intestinal bleeding and perforation are also less common.
Infant and toddler cold-damage disease is often atypical, and the course of the disease varies in severity. The onset is acute, accompanied by vomiting, convulsions, irregular high fever, rapid pulse, abdominal distension and fullness, diarrhea, etc. Rose spots are rare, and the white blood cell count is often increased. Complications such as bronchitis or pneumonia are quite common.
(5) Geriatric cold-damage disease Body temperature is often not high, symptoms are mostly atypical, and signs of weakness are prominent. Complications such as bronchopneumonia and cardiac insufficiency are common, and persistent intestinal dysfunction and memory impairment often occur. The course of the disease is prolonged, recovery is difficult, and the mortality rate is relatively high.
Relapse and recrudescence: Relapse occurs 1–2 weeks after symptoms disappear, with clinical manifestations similar to the initial episode, and blood culture turning positive again. The symptoms of relapse are milder, and the course is shorter, related to the massive proliferation of latent pathogens in the gallbladder or reticuloendothelial system, which re-invade the bloodstream. Relapse is more likely to occur when treatment is insufficient or the body's resistance is low. Occasionally, relapse may occur 2–3 times. Recrudescence refers to a recurrence of fever during the course of the disease, where the temperature rises again after gradually declining, returning to normal after 5–7 days. Blood culture is often positive, and the mechanism is similar to the initial onset.
bubble_chart Auxiliary Examination
(1) Routine Examination The white blood cell count is mostly 3×109/L to 4×109/L, accompanied by neutropenia and eosinophil disappearance, with the latter gradually rebounding as the condition improves. During the critical phase, if eosinophils exceed 2% or the absolute count surpasses 4×108/L, cold-damage disease can be largely ruled out. Grade I proteinuria may occur during high fever. Fecal occult blood tests are positive.
(2) Bacteriological Examination ① Blood culture is the definitive diagnostic evidence and can be positive early in the course of the disease. The positivity rate reaches 90% by days 7–10 of illness, drops to 30–40% in the third week, and is often negative by the fourth cycle of day and night. ② Bone marrow culture has a higher positivity rate than blood culture, especially suitable for patients already treated with antibiotics who test negative in blood culture. ③ Stool culture can yield positive results from the incubation period, with positivity rates as high as 80% in weeks 3–4. The positivity rate declines rapidly after 6 weeks of illness, though 3% of patients may continue shedding bacteria for over a year. ④ Urine culture: The positivity rate can reach 25% in the late stage (third stage) of the disease, but fecal contamination should be avoided. ⑤ Scrapings or biopsy specimens from rose spots may also yield positive cultures.
(3) Immunological Examination
1. Widal Test The serum agglutination test for cold-damage disease, known as the Widal reaction, has auxiliary diagnostic value for cold-damage disease and paratyphoid fever. The test uses five antigens: the somatic (O) antigen of cold-damage disease bacilli, the flagellar (H) antigen, and the flagellar antigens of paratyphoid A, B, and C. The aim is to measure the agglutination titers of various antibodies in the patient's serum using the agglutination method. Positivity is rare in the first week of illness but gradually increases from the second week, reaching 90% by the fourth week. Positive reactions may persist for months after recovery. A small number of patients may show delayed antibody elevation or persistently low antibody titers (14.4%) or negative results (7.8–10%) throughout the illness, so the disease cannot be excluded based on this alone.
The Widal test has been used for nearly 100 years. In the 1960s, its specificity was questioned due to inconsistent and ambiguous results. Non-cold-damage disease febrile conditions, such as various acute infections, tumors, connective tissue diseases, and chronic ulcerative colitis, can also yield positive Widal test results. Perlman et al. suggested that sterile colon cells and enterobacteria may share common antigens, and anti-colon antibodies produced by colon mucosal damage may cross-react with Salmonella somatic antigens. Therefore, the interpretation of Widal test results should be cautious and closely integrated with clinical data. It is also important to compare antibody titers during the convalescent stage. Some propose using locally prevalent strains instead of international standard strains to improve the positivity rate of cold-damage disease diagnosis in endemic areas.
2. Other Immunological Tests
(1) Passive Hemagglutination Assay (PHA): Red blood cells sensitized with cold-damage disease bacilli somatic antigens react with the test serum, and the presence of cold-damage disease-specific antibodies is determined based on red blood cell agglutination. Domestic and international reports indicate a positivity rate of 90%–98.35% and a false-positive rate of about 5%. Bao Xinghao et al. reported that LSP-PHA detected 89.66% of blood culture-confirmed cold-damage disease cases, 90.02% of early-stage patients, and 82.5% of clinically confirmed cases. Since it primarily detects specific IgM antibodies, it can be used for early diagnosis.
(2) Counter Immunoelectrophoresis (CIE): This method detects soluble cold-damage disease antigens or antibodies in serum. It is simple to perform, suitable for grassroots implementation, and highly specific, though its sensitivity is relatively low, with reported rates ranging from 24% to 92%. Results are most reliable when serum is collected during the initial stage (first stage) of illness, making it useful for early diagnosis of cold-damage disease.
(3) Coagglutination Test (COA): Utilizing the principle that Staphylococcus aureus protein A (SPA) can bind to the Fc segment of IgG antibodies, the test first sensitizes SPA-carrying Staphylococcus aureus with cold-damage disease antibodies, then reacts with the antigen. The positive rate of this test ranges from 81% to 92.5%, with a specificity of 94% to 98%. Generally, its sensitivity is higher than that of CIE, but its specificity is inferior to CIE.
(4) Immunofluorescence Test (IFT): Doshi et al. used a suspension of Vi antigen from cold-damage disease bacilli as the antigen for indirect immunofluorescence antibody testing. Among 140 blood culture-positive cold-damage disease patients, 134 (95.7%) tested positive; only 4 out of 394 controls (1%) showed false positives. Currently, there are few reports on this method. Whether cold-damage disease vaccination and other Salmonella infections affect the specificity of this test requires further study.
(5) Enzyme-Linked Immunosorbent Assay (ELISA): The basic principle of ELISA is to amplify primary immunological reactions through enzymatic reactions, enabling the detection of both antigens and antibodies. When detecting Vi antigen in cold-damage disease patients, ELISA has a sensitivity of 1 ng/ml, significantly higher than the CoA method's 9100 ng/ml, and can detect Vi antigen in urine diluted up to 1:1024. Domestic and international studies have used ELISA to detect clinical samples for Vi antigen, V9 antigen, LPS, H antigen, etc., with sensitivities ranging from 62.5% to 93.1%, depending on the antigen tested, with most exceeding 80%. Hangzhou's Bao Xinghao et al. simultaneously detected IgM and IgG antibodies using ELISA. The sensitivity and specificity of LPS-IgM-ELISA were 91.38% and 99.02%, respectively, while LPS-IgG-ELISA showed 93.1% and 98.02%. Among serological diagnostic methods for cold-damage disease, ELISA is recognized as a simple, rapid, sensitive, and highly specific diagnostic approach.
(IV) Molecular Biology Diagnostic Methods
1. DNA Probe: A DNA probe is a diagnostic reagent prepared from DNA to detect or identify specific bacteria. The method involves hybridizing a labeled, specific DNA fragment (probe) with denatured bacterial DNA in a sample, determining the presence of hybridization to achieve detection. Since the probe is prepared from a unique, bacteria-specific gene fragment, its specificity is very high. When detecting cold-damage disease bacilli cultured from samples, the sensitivity requires at least 1000 bacteria for detection. DNA probes exhibit high specificity but low sensitivity and are generally used for bacterial identification and isolation.
2. Polymerase Chain Reaction (PCR): PCR is a molecular biology method developed in the mid-to-late 1980s. It can amplify target genes or DNA fragments millions of times in vitro within hours, with a detection rate 100 to 10,000 times higher than DNA probes. Jae HS et al. used PCR to amplify the flagellar antigen-coding gene of cold-damage disease, achieving a sensitivity of detecting as few as 10 cold-damage disease bacteria and 100% specificity. Due to its high sensitivity, PCR is prone to product contamination, making the control of false positives and negatives critical for improving accuracy.
The clinical diagnosis of cold-damage disease can be made based on epidemiological data, clinical course, and immunological test results, but the definitive diagnosis of cold-damage disease relies on the detection of the pathogenic bacteria.
(1) Diagnostic Criteria
1. Clinical Diagnostic Criteria During the epidemic season and in endemic areas, persistent high fever (40–41°C) lasting for 1–2 weeks or longer, accompanied by a characteristic toxic appearance, relative moderate pulse, rose spots on the skin, hepatosplenomegaly, low total white blood cell count in peripheral blood, disappearance of eosinophils, and the presence of cold-damage disease cells (signet-ring cells) in the bone marrow smear, can clinically diagnose cold-damage disease.
2. Definitive Diagnostic Criteria Suspected cases can be confirmed if any one of the following criteria is met.
(1) Isolation of cold-damage disease bacilli from any specimen, including blood, bone marrow, urine, feces, or scrapings from rose spots.
(2) Positive serum-specific antibodies, with a Widal test showing an "O" antibody agglutination titer ≥1:80, an "H" antibody agglutination titer ≥1:160, or a fourfold or greater increase in titer during the stage of convalescence.
(2) Differential Diagnosis In the early stage of cold-damage disease (within the first week), before characteristic manifestations appear, it should be differentiated from viral infections, malaria, leptospirosis, acute sexually transmitted disease toxic hepatitis, and other conditions.
During the peak period of cold-damage disease (after the second week), most cases lack typical cold-damage disease manifestations and must be differentiated from sepsis, foxtail millet granulomatous pulmonary subcutaneous node, brucellosis, endemic macula and papule cold-damage disease, subcutaneous node meningoencephalitis, malignant histiocytosis, and other conditions.
bubble_chart Treatment Measures
(1) General Treatment and Symptomatic Treatment After admission, patients should be isolated as per gastrointestinal pestilence. Stool cultures should be sent for testing every 5–7 days after clinical symptoms disappear, and isolation can be lifted after two consecutive negative results. During the fever period, patients must rest in bed. They may sit up slightly 2–3 days after the fever subsides and engage in grade I activities two weeks after the fever subsides.
A high-calorie, high-nutrition, and easily digestible diet should be provided, including sufficient carbohydrates, proteins, and various vitamins to compensate for the consumption during the fever period and promote recovery. During the fever period, a liquid or fine, residue-free diet is recommended, with small, frequent meals. After the fever subsides and appetite improves, patients can gradually transition to congee and soft rice. Hard or high-residue foods should be avoided to prevent intestinal bleeding and perforation. A normal diet can generally be resumed two weeks after the fever subsides.
Patients should be encouraged to drink plenty of fluids, approximately 2000–3000 ml per day (including dietary intake), to facilitate toxin excretion. For those unable to eat due to severe illness, 5% glucose saline can be administered intravenously.
For patients with severe toxemia, corticosteroids may be used in conjunction with adequate and effective antimicrobial therapy. Commonly used regimens include hydrocortisone 25–50 mg or dexamethasone 1–2 mg, administered intravenously once daily; or oral prednisone 5 mg, 3–4 times daily, for a course not exceeding 3 days.
If cold-damage disease is complicated by schistosomiasis, especially acute schistosomiasis, adrenal corticosteroids should generally be used first in combination with pathogen-targeted treatment for cold-damage disease. Only after the body temperature is controlled and the overall condition significantly improves should oral praziquantel be administered to treat schistosomiasis.
For patients with both toxemia and significant bloating or diarrhea, corticosteroid use should be cautious to avoid intestinal bleeding and perforation.
(2) Selection of Antimicrobial Agents for Cold-Damage Disease
1. Fluoroquinolones are the first choice. Fluoroquinolones share the following characteristics: ① Broad-spectrum antibacterial activity, particularly high efficacy against Gram-negative bacilli; ② Low incidence of bacterial resistance due to mutation; ③ Wide distribution in the body, with high concentrations in tissues and body fluids, reaching effective bacteriostatic or bactericidal levels; ④ Most formulations are oral, making them convenient to use; ⑤ Due to their impact on bone development, they should be used with caution in pregnant women, children, and breastfeeding women. Commonly used agents include ofloxacin (dose: 300 mg twice daily orally or 200 mg every 8–12 hours intravenously, course: 14 days) and ciprofloxacin (dose: 500 mg twice daily or every 8 hours orally or intravenously, course: 14 days).
2. Cephalosporins: Second- and third-generation cephalosporins exhibit strong antibacterial activity against cold-damage disease bacilli in vitro, with low toxicity and side effects. They are particularly suitable for pregnant women, children, breastfeeding women, and cases of chloramphenicol-resistant cold-damage disease. Options include ceftriaxone (dose: adults 1 g every 12 hours, children 100 mg/kg daily, course: 14 days) and cefotaxime (dose: adults 1–2 g every 8–12 hours, children 100–150 mg/kg daily, course: 14 days).
3. Chloramphenicol: Dose: 25 mg/kg daily, divided into 2–4 oral or intravenous doses. After body temperature normalizes, the dose should be halved. Course: 2 weeks. Precautions: ① Contraindicated in newborns, pregnant women, and those with significant liver impairment; ② Monitor for toxic side effects, and regularly check blood counts. Discontinue if white blood cells fall below 2500/mm³. 3 4. Ampicillin (or Amoxicillin): Dose: adults 2–6 g/day, children 100–150 mg/kg daily, divided into 3–4 oral or intravenous doses. Amoxicillin: adults 2–4 g/day, divided into 3–4 oral doses. Course: 14 days. Precautions: ① The efficacy of these drugs is suboptimal, so the course should be prolonged to reduce relapse and bacterial shedding. ② Discontinue immediately if a drug rash occurs.
5.Compound formula Sulfamethoxazole dose: Adults, 2 tablets twice daily; Children, SMZ 40~50mg/kg per day, TMP 10mg/kg per day, twice daily. Course of treatment: 14 days.
(III) Treatment of Carriers
1. Ampicillin (or Amoxicillin) Dose: For adults, ampicillin 4–6 g/day or amoxicillin 6 g/day plus probenecid 2 g/day, divided into 3–4 oral doses. Course: 6 weeks.
2. Ofloxacin or Ciprofloxacin Dose: Ofloxacin 300 mg twice daily, or ciprofloxacin 500–750 mg twice daily, orally. Course: 6 weeks.
(IV) Treatment of Complications
1. Intestinal Hemorrhage ① Strict bed rest, closely monitor blood pressure, pulse, mental status, and hematochezia; ② Temporarily withhold food or provide small amounts of liquid diet; ③ Intravenous infusion of glucose saline, maintain electrolyte balance, and add hemostatic agents such as vitamin K, adrenobazone, aminomethylbenzoic acid, and hemostatic powder; ④ Transfuse blood as needed based on bleeding severity; ⑤ If the patient is dysphoric or restless, administer sedatives such as diazepam or phenobarbital sodium, but avoid laxatives and enemas; ⑥ If bleeding persists despite aggressive treatment, consider surgical intervention.
2. Intestinal Perforation Except for localized cases, patients with intestinal perforation complicated by peritonitis should undergo prompt surgical treatment, combined with adequate and effective antibiotics such as chloramphenicol or ampicillin plus gentamicin or kanamycin to control peritonitis.
3. Toxic Myocarditis Strict bed rest, supplemented with adrenal corticosteroids, vitamin B1, ATP, and intravenous hypertonic glucose solution. If heart failure occurs, manage it aggressively with digitalis and furosemide, maintaining treatment until clinical symptoms improve. However, patients may have poor tolerance to digitalis, so use with caution.
4. Toxic Hepatitis In addition to liver-protective therapy, adrenal corticosteroids may be added.
5. Cholecystitis Treat according to general internal medicine protocols.
6. Hemolytic Uremic Syndrome ① Control the primary infection with cold-damage disease bacilli using ampicillin or amoxicillin; ② Administer blood transfusions and fluid replacement; ③ Use corticosteroids such as adrenocorticotropic hormone, dexamethasone, or prednisolone, which can rapidly alleviate symptoms, especially in pediatric patients; ④ Anticoagulation therapy, such as low-dose heparin (50–100 U/kg daily) via intravenous injection or infusion, is highly effective for controlling this syndrome. Alternatively, low-molecular-weight dextran may be used; ⑤ If necessary, perform peritonitis dialysis or hemodialysis to promptly clear azotemia and promote renal function recovery.
7. DIC Provide anticoagulation therapy, transfuse blood as needed, and use ampicillin to control the primary infection.
The prognosis of cold-damage disease is related to the patient's condition, age, presence of complications, timing of treatment, treatment methods, whether they have received preventive vaccinations in the past, and the virulence of the pathogen.
Before the application of effective antibacterial drugs, the mortality rate was about 20%. Since the use of chloramphenicol, the mortality rate has significantly decreased to approximately 1–5%. The prognosis is poorer in the elderly and infants, as well as in those with significant anemia or malnutrition. Complications such as intestinal perforation, intestinal hemorrhage, myocarditis, and severe toxemia are associated with higher mortality rates. In a domestic group of cold-damage disease and paracold-damage disease cases, among 38 deaths, intestinal perforation accounted for 39.5%, toxemia 39.5%, myocarditis 9.9%, toxic shock 5.3%, intestinal hemorrhage 2.6%, pneumonia 2.6%, and heart failure 2.6%. Patients who have received preventive vaccinations tend to have milder symptoms and a better prognosis.
The key is to strengthen dietary and water hygiene, as well as fecal management, to cut off transmission routes. Patients and carriers should be isolated as per intestinal pestilence until one week after stopping medication, with weekly stool cultures conducted until two consecutive negative results are obtained. The long-used inactivated vaccine offers suboptimal protection, while an oral attenuated vaccine is currently under trial.
In recent years, the complications of internal damage cold domestically have significantly decreased, but foreign reports indicate an increasing trend of cold-damage disease complicated by hemolytic uremic syndrome, and cases complicated by DIC are not uncommon, which should raise vigilance.
1. Intestinal hemorrhage: A common complication, with an incidence of about 2.4–15%, mostly occurring in the 2nd–3rd week of the disease course. It can range from occult blood in stool to massive hematochezia. Minor bleeding may be asymptomatic or only cause grade I dizziness and rapid pulse; massive bleeding may lead to a sudden drop in fever, thready and rapid pulse, a crossover phenomenon in the temperature and pulse curves, as well as dizziness, pale complexion, dysphoria, cold sweating, and a drop in blood pressure, presenting as shock. Patients with diarrhea have a higher chance of intestinal hemorrhage. During the disease course, factors such as getting up and moving around arbitrarily, a diet high in solid and fibrous residues, excessive eating, excessive straining during defecation, and therapeutic enemas can all be triggers for intestinal hemorrhage.
2. Intestinal perforation: The most severe complication, with an incidence of about 1.4–4%, mostly occurring in the 2nd–3rd week of the disease course. Intestinal perforation often occurs in the terminal ileum but can also be seen in the colon or other intestinal segments; most cases involve a single perforation, with a few having 2–3, and some reports even mention up to 13 perforations. The manifestations of intestinal perforation include sudden severe pain in the right lower abdomen, accompanied by nausea, vomiting, cold sweating, thready and rapid pulse, shortness of breath, and a drop in temperature and blood pressure (shock phase). After 1–2 hours, the abdominal pain and other symptoms may temporarily ease (calm phase). Soon after, the temperature rises rapidly again, and signs of peritonitis appear, including abdominal distension and fullness, persistent abdominal pain, abdominal wall tension, widespread tenderness and rebound tenderness, weakened to absent borborygmi, free fluid in the abdominal cavity, free gas under the diaphragm on X-ray, and an increased white blood cell count with a left shift (peritonitis phase). The triggers for intestinal perforation are roughly the same as for intestinal hemorrhage, and some cases may experience intestinal perforation concurrently with intestinal hemorrhage.
3. Toxic myocarditis: Incidence of 3.5–5%, commonly seen in the 2nd–3rd week of the disease course in patients with severe toxemia. Clinical features include an accelerated heart rate, weakened first heart sound, arrhythmia, premature beats, diastolic gallop rhythm, and low blood pressure. Electrocardiogram shows prolonged P-R interval, T-wave changes, and S-T segment deviations. These symptoms, signs, and ECG changes normalize as the condition improves. However, there are reports of cold-damage disease patients still suffering from complete atrioventricular block and even grade I Adams-Stokes syndrome one year after recovery.
4. Toxic hepatitis: Incidence of about 12.8–60%, commonly seen in the 1st–2nd week of the disease course. The main features are hepatomegaly, which may be accompanied by tenderness, and a few cases (0.4%–26.6%) may develop grade I jaundice, with mildly elevated transaminase activity, while flocculation and turbidity tests are generally normal. Clinically, it can easily be confused with viral hepatitis or amebic hepatitis. As the condition improves, hepatomegaly and liver function usually return to normal within 2–3 weeks, with only rare cases developing life-threatening hepatic encephalopathy due to severe jaundice.
5. Hemolytic uremic syndrome: In recent years, foreign reports indicate an increasing trend in incidence, reaching 12.5%–13.9%, with sporadic domestic reports as well. It generally occurs in the 1st–3rd week of the disease course, with about half of cases occurring in the first week. The main manifestations are hemolytic anemia and renal failure, along with increased fibrin degradation products, thrombocytopenia, and red blood cell fragmentation. The occurrence of this syndrome is unrelated to the severity of cold-damage disease, the presence of G-6PD deficiency in the patient’s red blood cells, or the use of chloramphenicol. It may be caused by the cold-damage disease bacillus endotoxin inducing microvascular coagulation in the glomeruli.
In addition to the above complications, cold-damage disease bacillus can also cause pulmonary infections, acute cholecystitis, hemolytic anemia, DIC, and other conditions.
