Answer to Q1

Differential diagnosis of: skin lesions on the legs, febrile systemic illness and mild raised liver enzymes in a returning traveller from Rome and the Amalfi coast?

Skin rashes in returning travellers are as common as in the general population anywhere in the world. One could consider an allergic rash/ fixed drug eruption – from a change in detergent or from the vegetation in that area. This does not however present with raised liver enzymes and febrile illness.

Malaria - Malaria should always be considered in the febrile returning traveller. However, although it has recently been reported in Greece, Italy is not recognized as an endemic country. The history of rash would not fit and would suggest a second pathology. It is however worth considering that malaria was at one time endemic throughout much of Italy. P. falciparum transmission ceased in 1950 after an intensive vector control campaign; The last autochthonous case of P. vivax was documented in 1955 in Calbria. The last endemic focus of P. vivax was reported in Sicily in 1956. Much of southern and central rural Italy remains receptive to malaria transmission due to the presence of capable malaria vectors such as An. labranchiae. While the overall malariogenic potential appears to be low and the reintroduction of malaria unlikely, the densities of An. labranchiae remain very high, along with other potential vectors as An. maculipennis, An. atroparvous and An. superpictus. Most of these species are not particularly receptive to African strains of P. falciparum. However, after a 20 year absence, P vivax was reintroduced in Maremma, Italy in 1977 diagnosed in a woman with no history of travel. Investigation identified a 7-year-old girl who had travelled to India as carrying P vivax. Her parents were also infected.

Vector-borne infections

• There are numerous insect and tick vectors that should be considered, some of which may cause an infectious disease manifesting with fever and systemic illness. These include:
• Flea bites causing Murine typhus. Fleas often proliferate in empty housing such as holiday homes. New inhabitants present very welcome victims. Although some of the symptoms resemble those of murine or endemic typhus, including raised liver enzymes and the incubation period, he did not present with a rash over his body. The full blood count that he had was normal – no anaemia or low platelets.
• Murine typhus, whose causative agent is Rickettsia typhi, has a worldwide distribution. In Europe, the main reservoir is the rat Rattus norvegicus and the most common flea vector is the Oriental rat flea, Xenopsylla cheopis, and, less frequently, the cat flea Ctenocephalides felis. Transmission occurs by contamination with rickettsia-containing flea faeces or tissue during or after blood feeding by the flea.
  
  Murine typhus is usually a benign, acute, febrile disease characterized by headache, nausea, body aches and fever which persists for about 12 days. The incubation period for murine typhus is 6 to 14 days. Five or six days after the initial symptoms, a rash that starts on the trunk of the body and spreads to the arms and legs, appears. If left untreated, the disease may last for several months. Mortality is low and more common in elderly patients. Misdiagnosis is frequent and the infection is probably much more common than reported. In Europe, murine typhus has been reported from Bosnia and Herzegovina, Croatia, the Czech Republic, France, Greece, Italy, Portugal, the Russian Federation, Serbia and Montenegro, Slovakia, Slovenia and Spain, and is likely to be present in most other countries as well. An FBC may show anemia & thrombocytopenia. Hypoalbuminaemia, hyponatraemia, high typhus antibody titres and generally mild renal and hepatic dysfunction may manifest. Treatment includes either a tetracycline (doxycycline) or less commonly, chloramphenicol.
• Tick-borne infections:
• Tick-borne Rickettsioses endemic to or reported in Europe include Mediterranean spotted fever (Tick typhus or Boutonneuse Fever), more than one species of Ehrlichiosis, Rickettsial Pox, and Q Fever.
• Mediterranean spotted fever (MSF) Caused by Rickettsia conorii transmitted in Europe by the ‘brown dog tick’ Rhipicephalus sanguineus, although other species of ticks may occasionally be found infected as well. The infection is endemic in the Mediterranean area of Europe and throughout many parts of Africa and Asia. Patients usually present with fever, malaise, generalized maculopapular rash and a typical eschar or “Tache Noir”. While the disease is usually mild, serious forms, including encephalitis, while infrequent, do occur, and they are associated with a high mortality rate; in a review of 199 serologically confirmed cases, reported a mortality rate of 2.5%.
  
  Mediterranean spotted fever and African tick bite fever (ATBF) are different illnesses in the same geographic area. ATBF is caused by R. africae and classically presents with local adenopathy and multiple eschars, whereas MSF does not.
• Tick-borne encephalitis (TBE) is the most important and widespread of the arboviruses transmitted by ticks in Europe. It is a member of the family Flaviviridae. TBE should be considered a general term encompassing at least three diseases caused by similar flaviviruses, whose range spans an area from the British Isles (Louping ill, an encephalomyelitis of sheep), across Europe (central European tick-borne encephalitis), and to the Far East of Russia (Russian spring-summer encephalitis).
  
  Man is infected by the bite of infected ticks and, much more rarely, by the ingestion of fresh milk from infected domestic animals. TBE is often the cause of a serious acute central nervous system (CNS) disease that may result in death or long-term neurological sequelae for a considerable period after recovery from the initial infection. The disease may take the form of meningitis, meningoencephalitis, meningoencephalomyelitis, or meningo-radiculitis. Although a handful of cases have been reported in Italy, TBE is not known to occur in the Amalfi area.
• Crimean Congo Haemorrhagic Fever has not been recorded this far south in Europe and does not present with multiple tick bites or the relatively mild symptoms this patient suffered from.
  
  Lyme disease – The presentation of the skin lesions and the systemic symptoms does not fit in with Lyme disease. Lyme borreliosis, or Lyme disease (LD), is the most commonly reported tick-borne infection in Europe and North America, and, indeed, the most commonly reported vector-borne disease. The disease is a multi-system disorder that can affect a complex range of tissues including the skin, heart, nervous system, and, to a lesser extent, the eyes, kidneys and liver. Its incidence is increasing in many parts of Europe. In Italy, the seroprevalence of antibodies to B. burgdorferi in patients or in at-risk subjects varies between 0.2 and 22%.
• A range of other exotic sounding viruses are known to cause illness after bites from infected ticks in Europe, including parts of Italy: Bhamja, Thogoto, Tribec and Dhori virus spring to mind. (or not…)
• Sandfly-borne infections
• Leishmaniasis - although cutaneous leishmaniasis does occur in Italy, the patient’s symptoms are not indicative of this infection and neither is the incubation period which is usually >3 months.
• Pappataci / Three day Fever In Central and Southern Italy, three sandfly fever viruses (Naples, Siciliana, Toscana) are transmitted by Phlebotomus spp, and cause an illness locally known as Pappataci or Three-day fever. Serotype Naples and Sicilian viruses are the aetiologic agents of a usually mild, self-limited disease characterized by fever, myalgia, and headache.

In the absence of a definitive diagnosis based on the available laboratory tests in South Africa, the authors conferred with two Italian infectious disease specialists with an interest in travel health. They confirmed that Pappataci fever has been documented in the Amalfi area in the recent past. The fact that the patient was by then recovering fitted the typical clinical outcome of the disease. They did not feel that there was any reason to go to great lengths to make a laboratory diagnosis.

Currently laboratory diagnosis is not available in the private or public sector in South Africa.

Pappataci Fever

Pappataci is the Italian word for sandfly. Three serotypes of Phlebovirus, Naples virus, Sicilian virus and Toscana virus are known causative agents.

Pappataci fever, or Sandfly Fever as it is commonly known is common in the subtropical zone of the Eastern Hemisphere between 20°N and 45°N, particularly in Southern Europe, North Africa, the Balkans, Eastern Mediterranean, Iraq, Iran, Pakistan, Afghanistan and India.

Distribution of Pappataci Fever by serotype. (T, Toscana, S, Sicilian, N, Naples).

Naples and Sicilian are the viruses largely responsible. Both were isolated by Sabin (of Polio fame) during World War II. The two infections frequently overlap. They were the cause of a very large number of illnesses among troops operating in the endemic area during both World Wars. After the Second World War and with the application of DDT residual sprays for the control of malaria vectors, Sicilian and Naples viruses virtually disappeared. The incidence of these two viruses remains high in most of their other endemic areas. Toscana virus is now known to be widely distributed in Italy, and has been reported from Portugal, Cyprus and Spain;

The sandfly-transmitted viruses are all Phleboviruses within the Bunyavirus group. Globally, some 45 viruses are associated with sandflies. Some Phleboviruses are transmitted by mosquitoes, e.g. Rift Valley fever, whereas others are transmitted by ticks.

Important vectors include Phlebotomus papatasi (see photo), Phlebotomus perniciosus and Phlebotomus perfiliewi. The sandfly becomes infected when biting an infected human in the period between 48 hours before the onset of fever and 24 hours after the end of the fever, and remains infected for its lifetime. Besides this ‘horizontal’ virus transmission from man to sandfly, the virus can be transmitted transovarially, from an infected female sandfly to its offspring.

Pappataci fever is seldom recognised in endemic populations because it is mixed with other febrile illnesses of childhood, but it is better known among immigrants and military personnel from non-endemic regions.

There is a high rate of asymptomatic infection. In those that develop symptoms a few days after the infective bite, a feeling of lassitude, abdominal distress and chills develop followed by fever of 39°C to 40°C, severe frontal headaches, muscle and joint aches, flushing of the face and tachycardia. After two days the fever begins to subside and the temperature returns to normal. Fatigue, bradycardia and subnormal blood pressure may persist from a few days to several weeks but complete recovery is the rule.

Although normally a mild self-limiting disease, Pappataci fever has been associated with acute neurologic disease, and clinical cases of aseptic meningitis or meningo-encephalitis. Toscana virus may be responsible for up to 80% of acute viral CNS infections during the Italian summer.

The importation of sandfly fevers by tourists and soldiers returning from endemic areas is a growing problem with less than 20% of actual infections correctly diagnosed by physicians.

Diagnosis: Commercial tests are not readily available - diagnosis can only be confirmed by serology-based assays or real-time PCR in laboratories that have developed assays to perform such identification.

Treatment is symptomatic only.

Prevention of sandfly bites, and control of sandflies and their breeding grounds with insecticides are the principal methods for prevention. Mosquito nets are not effective to prevent sandfly bites as they are not only night biting and occur on sandy areas - such as beaches and desert dunes. DEET is an effective insect repellent that will also decrease sand fly bites.

Question 2: How would you investigate this patient?