A 35 year Port Elizabeth resident presented with haematemesis 4 days after the onset of fever and myalgia. He gave a history of frequent travel to the major cities in the course of his work as a pilot. He also goes hunting most weekends in the Aberdeen area of the Eastern Cape.
A gastric bleed was suspected and he was referred to the surgical unit. Blood results taken pre- gastroscopy were:
A 19 year old university student traveled on a football tour to the Northern Cape for the past 7 days and returned last night. During the tour they stayed in hostels in various towns and also visited a farm for a farewell braai the night before the last match. On the day of his return he scored 4 goals in a match at the University.
At lunch time he complained of feeling unwell and feverish. By 16h00 he was vomiting, had a temp of 40C and seemed a b it sleepy. At 21h00 he was taken to hospital with bruising of the skin. By midnight he was hypotensive, semi-comatose and bleeding from puncture and intravenous catheter sites. At 01h00 hrs he had a cardio respiratory arrest requiring resuscitation.
Blood results on admission:
A 38 year old man from Johannesburg presented with a one week history of fever and nausea and abdominal pain for which he had taken symptomatic treatment. On day 7 of his illness he was confused with a temperature of 40C, and had no skin lesions / rashes. He was previously completely well, and had a history of travel 1 month ago to the Kruger Park. Over the next 24 hours he became hypotensive, developed ARDS, was bleeding everywhere with DIC, and went into renal failure Initial blood results:
Question 1: What are the important differential diagnoses?
Answer to Q1
Viral haemorrhagic fever.
Viral hemorrhagic fevers (VHFs) in humans result from infection with RNA viruses belonging to four families (Table 1). The incubation period varies from 2 to 21 days. Although the clinical presentations may vary, some common features of the initial disease manifestation include high fever, malaise, myalgia, headache and abdominal pain. As the disease progresses the patient may present with vomiting, mucosal (including gastrointestinal) bleeding, altered mental state, skin rashes, oedema, and hypotension.
Rift Valley fever (RVF) and Crimean-Congo hemorrhagic fever (CCHF) are both caused by arthropod-borne viruses. RVF is transmitted to humans by mosquitoes and by direct contact with body fluids of sick animals (Lambs, goats, cattle). RVF is often asymptomatic, and probably < 1% those infected present with a VHF-like picture. There was an outbreak of RVF in the first half of 2010, and as of April 2011, 20 human cases have been confirmed, mainly in the Eastern and Western Cape.
CCHF is thought to be the most common VHF in South Africa and occurs most frequently in the Kimberly area. Humans may acquire infection through contact with blood and tissues of a viraemic animal, another human case or through the bite of an infected tick. The disease in South Africa is transmitted by ticks of the Hyaloma species such as bont-poot bosluis (striped leg tick). Approximately 10-12 cases of CCHF occur in humans annually in South Africa.
Table 1: Common viral causes of haemorrhagic fever
The other viral haemorrhagic fevers do not normally occur in South Africa, although imported cases have been described and have been responsible for nosocomial outbreaks. The mortality rate for disease such as Ebola can be as high as 80%. None of the cases presented here had travelled outside of South Africa, and thus Ebola, Lassa and Marburg would not normally be considered in the differential.
In case 1, the history of travel and hunting is an important clue. The presentation with a prodromal illness preceding the bleeding is fairly typical of Congo Fever, as are the laboratory findings of thrombocytopaenia, leucopenia and mildly elevated transaminases. This patient was in fact confirmed to have Crimean-Congo haemorrhagic fever.
In case 2, there is also a travel history. However, the clinical presentation is atypical of CCHF. The patient developed shock and bleeding all in under 24 hours, with no evidence of prodromal illness. Transaminases are essentially normal. While this doesn’t exclude CCHF, it makes it less likely. However, the travel history means that CCHF must be part of the differential
In case 3, the patient had travelled to the Kruger National Park. This is not a high risk area for CCHF, but he could have acquired Rift Valley Fever here (although again, the Kruger Park is slightly outside the area of reported cases). Although most cases of RVF are probably mild or asymptomatic, fulminant cases have been described, and fulminant hepatitis has been a feature of some of the severe cases. Against Rift Valley Fever is the fact that travel occurred a month ago, which is probably too long for the incubation period for Rift Valley Fever. However, it would be prudent to keep VHF on the list of differentials.
Meningococcaemia can present with fulminant sepsis, fever, hypotension, thrombocytopaenia with haemorrhage, and ecchymoses. The incidence of meningococcal disease in South Africa in 2009 was approximately 0,94 / 100 000, with a case fatality rate of about 15%..
Neisseria meningitidis is spread primarily by the droplet route, and close household contacts of cases are at an approximately 400 fold increased risk of developing symptomatic infection. This is probably due to a combination of shared environmental factors (eg smoking), possibly genetic factors, and transmission of the organism from asymptomatic carriers. However, spontaneous community cases still account for the vast majority of meningococcal disease, thus the absence of a history of exposure by no means rules the condition out
In Case 1, the progression of the illness is if anything, slightly slow for meningococcal infection. In case 2, the fulminant presentation makes meningococcal infection probably the most likely differential diagnosis. The travel history is thus a red herring. The fact that the patient is a university student and stayed in hostels is more important from the point of view of subsequent infection control advice. This patient did in fact have severe meningococcal sepsis.
In case 3, again, the history of a week’s fever, abdominal pain and nausea, followed only later by ARDS, DIC and shock, are atypical of meningococcal infection.
Tick bite fever (Rickettsial infection).
Probably the two commonest causes of tick bite fever in South Africa are Rickettsia conorii and Rickettsia africae. The infection is spread by the bite of Amblyomma ticks, and usually occurs after exposure in a rural environment. The clinical presentation is usually that of a fever and headache, and in R. africae infection, an eschar is almost always present. Rash is also an important clue, although may not be present in all cases. This differential should be considered in all 3 cases given the travel history and possible tick exposure, however the absence of an eschar in all 3 arguably makes this diagnosis less likely. The rapid, fulminant presentation of case 2 would also be highly unusual for tick bite fever. In case 1 and 3, tick bite fever is slightly more likely.
Severe bacterial sepsis
Severe bacterial sepsis, usually Gram negative, can also present with fever and a DIC which may result in haemorrhagic manifestations. Any patient presenting with a fever and potential DIC should have blood cultures taken and be started on an antibiotic with Gram negative cover (such as a 3rd generation cephalosporin).
This is a zoonotic disease, with human infection occurring after direct contact with an animal’s urine or tissue, or indirectly after contact with contaminated water or soil. The disease has an incubation period of 2-20 days (usually 1-2 weeks), and clinically is typically biphasic. The septicaemic phase is usually acute in onset, with fever, chills, headache and muscle aches, and lasts 4-8 days, at which stage the symptoms defervesce. The immune phase then follows after 6-12 days, again with fever, headache and signs of meningitis.
Weil’s syndrome is a severe form of lepotspirosis, with jaundice, renal failure, anaemia, haemorrhages and altered levels of consciousness. Hepatic damage is usually minimal. Again, the rapidly fulminant course in case 2 makes this diagnosis less likely. It would however remain on the differential list for cases 1 and 3, although the degree of transaminitis in case 3 is maybe slightly unusual.
Cases have been described in South Africa; however, the true incidence is unknown. This is partly due to the fact that many cases resolve spontaneously, and partly due to the fact that symptoms are non-specific, and laboratory testing is probably not requested in all cases.
The markedly elevated transaminases make fulminant viral hepatitis the most likely diagnosis in case 3. Hepatitis A or B would be first on the list, however if these are excluded (as they were in case 3), then other viral causes would need to be sought, including agents such as CMV and herpes simplex. Hepatitis C is exceedingly rare in South Africa. The diagnosis in case 3 was in fact herpes simplex hepatitis.
Malaria must be strongly considered in the differential diagnosis of all the cases, and especially of case 3, given the travel history. Cases 1 and 2 did not give a strong history of travel to malaria endemic areas (they had travelled primarily in the Eastern and Northern Cape), and the severe fulminant presentation in case 2 would again be unusual for malaria. Other important question from the history would include whether prophylaxis was taken.
Question 2: Which of these differential diagnoses have important public health and /or infection control implications?
Answer to Q2
Which of these differential diagnoses have important public health and /or infection control implications? The two that have major infection control and public health implications are viral haemorrhagic fever and meningococcal infection.
Although person-to-person transmission is not the primary route of transmission of the arboviruses, they can be transmitted from person to person by contact with blood or blood stained secretions. It is not thought that the arboviruses that cause VHF can be spread by the airborne route, although droplet spread (especially if respiratory secretions are bloody) may be possible. In South Africa, community outbreaks of VHF are uncommon, although this has been described in other parts of Africa. However, there is certainly potential for nosocomial transmission, and given the high fatality rate of some of the VHFs, early recognition / suspicion is critical.
N. meningitidis is more likely to be involved in community outbreaks, especially if the index case comes from a setting where there many people are in prolonged close contact (eg military barracks, dormitories, hostels). Nosocomial transmission is probably less of a concern than in cases of VHF. However, HCWs can become exposed to the organism if they have close contact with the index case’s secretions, as may happen with mouth-mouth resuscitation or intubation. Therefore, again, a high index of suspicion is vital.
Both meningococcal disease and VHF are notifiable conditions, and both must be notified telephonically to the regional health authorities within 24 hours. Notification should occur on clinical suspicion, and does not need to wait for laboratory confirmation.
Question 3: What are the recommended public health and/or infection control interventions when faced with such cases?
Answer to Q3
Viral Haemorrhagic Fever
In 1998, the WHO published The 9 key points of VHF Isolation Precautions in order to limit VHF hospital outbreaks by preventing secondary cases of infection in health care facilities, and these have been adopted by the draft National Infection Control Policy, as follows:
The use of standard precautions in all patients
An infected person is not always obvious to a healthcare worker. Therefore standard precautions must be used with all patients. Standard precautions are designed to minimise exposure of HCWs to blood and body fluids as well as mucous membranes, and include the wearing of gloves and gowns when there is likely to be contact with body fluids, as well as use of face protection if splashes are likely. Other elements of standard precautions include safe waste disposal, safe disposal of sharps and hand hygiene.
After making a diagnosis of VHF, additional precautions must be employed.
Prompt identification of suspected cases of VHF
Suspicion and/or diagnosis of VHF before a recognisable outbreak is challenging. The early symptoms and signs are common to a wide range of other diseases (as illustrated by the differential diagnoses in the above cases). Therefore VHF may not be suspected until the patient develops more advanced signs.
If a patient has unexplained bleeding from mucus membranes (gum, nose, vagina), skin (puncture sites, petechiae), conjunctivae (red eyes) or gastro-intestinal system (vomiting blood, bloody or dark stools) associated with fever, and or shock, then the patient should be immediately isolated. Health care workers should have a high index of suspicion in endemic areas and in non-endemic areas (especially if there is a history of travel). Additionally, a history of contact with someone with fever and bleeding should be treated as highly suspicious of VHF. Important questions in the history include:
Immediate isolation of the suspected patient
Use protective clothing
All health care workers, support staff (such as cleaners), laboratory staff and family members who provide direct patient care to suspected VHF patients must wear protective clothing:
Used personal protective equipment must be appropriately disposed of after handling the patient.
Appropriate decontamination of all reusable supplies and equipment
The following must be decontaminated immediately after dealing with a suspected VHF infected patient:
Prepare a fresh disinfectant in advance. This is a bleach solution that contains 5% chlorine.
Safe disposal of waste
All contaminated waste produced in the care of VHF patient must be disposed of safely.
Safe burial practices
Health care workers should be aware of the family’s cultural and religious beliefs in order to counsel them appropriately and explain why some cultural practices relating to burial may have to be forbidden, including touching, cleaning or ritual purification of the body.
Remain vigilant to ensure the recommended burial procedure is followed.
Community education (in cases where there is a concern that the VHF may spread in the community)
Monitoring of contacts
A list of contacts of the index case must be compiled, including friends and family as well as HCWs who have been exposed to the index case. If any contacts are symptomatic (eg fever, myalgia), they should be isolated as above, and screened immediately. If they are asymptomatic, they should be monitored daily for 14 days after the last contact for the development of fever. If fever is documented, then they must be admitted, isolated and tested for the particular VHF
For meningococcal infection, patients should be isolated in a side room if possible, and all HCWs or visitors entering the room should wear surgical masks, as well as gloves and gowns. Goggles should also be worn if there is the chance of significant aerosolisation of respiratory secretions, as may happen with intubation or bronchoscopy. Isolation of the index case should continue for 24-48 hours after commencing treatment with a third generation cephalosporin (which will eliminate carriage). If the patient is treated with penicillin, then they will need chemoprophylaxis as outlined below to eliminate carriage as well, as penicillin is not very effective at clearing nasopharyngeal carriage of the organism. All close household contacts (including dormitory / hostel etc) contacts should be offered prophylaxis with ciprofloxacin (500mg stat for adults, or 10mg/kg stat for children < 12). alternatives include ceftriaxone intramuscularly (250mg stat for adults, 125 mg stat for children < 12), or rifampicin (usually only offered to children if there are concerns about using ciprofloxacin, 10mg/kg bd for two days). Health care workers need to be offered prophylaxis if they have come into close contact with respiratory secretions (as may happen during intubation, resuscitation etc).
Those who do NOT require prophylaxis, unless they meet other criteria for close contact, include:
Case 1: The patient was confirmed to have Crimean-Congo haemorrhagic fever. He started to recover from this, but then developed a nosocomial infection and died as a result.
Case 2: The patient had meningococcal infection, and despite extensive resuscitation attempts the patient died Case 3: The patient died from severe hepatic failure, as well as renal failure.
A high index of suspicion is always necessary in order to identify potential cases of VHF. The presentation is often not specific, and can be confused with a number of other, more common conditions. However delayed diagnosis increases the chance of nosocomial spread in the health care setting. Standard precautions should be applied to ALL patients, regardless of underlying disease.
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