Fever is a frequent problem after a stay in the (sub)tropics. A problem that occurs during or after a trip does not necessarily need to have a causal connection with that trip. Its cause can be a cosmopolitan disease, such as influenza, pneumonia, endocarditis or pyelonephritis. More exotic causes, such as dengue, malaria, liver amoebiasis, Katayama fever or melioidosis, are however also possible.
It is essential to know what countries the patient has visited. The travel history often yields important clues.
Example: There is no need to look for Chagas’ disease or scrub typhus in anyone who has travelled only in Africa and it is not necessary to look for Japanese encephalitis after a trip in Brazil. Bartonellosis should not be considered in the differential diagnosis after a stay in Laos, though it is certainly a possibility if the patient has acute haemolytic anaemia after a trip in the northern Andes. Contact with surface water can be of significance (e.g. leptospirosis, acute schistosomiasis).
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Enquiries should be made as to when the fever began. When someone is making their first visit to an area endemic for falciparum malaria, a fever within 6 days of arrival cannot be explained by falciparum malaria, typhoid fever, liver amoebiasis, African trypanosomiasis, Katayama syndrome, Chagas’ disease, deep mycoses or kala azar. Airport malaria is so rare that it poses a special problem.
Fever occurring later than 4 weeks after returning home automatically excludes a number of diseases with a short incubation period (arboviroses, typhus, leptospirosis, plague, acute bartonellosis). Malaria and kala azar can occur many months after leaving an endemic area.
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Inquiries must also be made about oral chemoprophylaxis (e.g. mefloquine). Plasmodium vivax, malariae and ovale malaria cannot occur while adequate prophylaxis is taken against P. falciparum malaria. However, after discontinuing the chemoprophylaxis an attack is possible if the patient has travelled in an endemic area. Adequately administered vaccination against yellow fever excludes this disease, but vaccination against typhoid fever only reduces the risk of the latter disease.
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After collection of the basic data, inquiries must be made as to whether an acute or a chronic disease is involved. No time must be lost if malaria is a possibility and if there are warning symptoms (diminished consciousness, oliguria, icterus, dyspnoea, vomiting).
Besides anamnesis and physical examination it is essential that a complete blood count and a thick smear are obtained. Combination of all these data leads to a preliminary diagnosis or a short list of differential diagnoses. In addition, liver and urine tests, haemocultures, a chest X-ray and an abdominal ultrasound can be performed. Serological tests are of no use at the beginning of a febrile disease. Serum may be frozen in order to detect seroconversion when a later blood sample (paired sera) is obtained.
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Rickettsiosis and dengue are frequent causes of cutaneous rash and fever after a trip in the (sub)tropics. Septicaemia due to meningococci is life-threatening. A disease that occurs after a trip does not necessarily need to have an exotic aetiology.
A distinction is often made between scarlatiniform, morbilliform, roseoliform, vesicular and petechial cutaneous rashes. As the same organism can cause different cutaneous abnormalities, an aetiological survey is given here.
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- Typhus or spotted fever
(rickettsiosis) occurs quite frequently. An inoculation chancre can be found in tick-bite fever and in scrub typhus. Transient leucopenia and thrombocytopenia characterise the disease. Rocky Mountain spotted fever and epidemic spotted fever are very serious diseases.
- Typhoid fever is a consequence of infection with Salmonella typhi. Roseola typhosa are discrete maculopapular lesions. They are rare and are usually difficult to detect. If they do occur they are found on the thorax and the abdomen.
- Secondary syphilis is accompanied by a maculopapular rash. Lesions occasionally appear simultaneously on the oral mucosa. Condylomata lata and alopecia areata should be looked out for. Serology is essential for diagnosis.
- Scarlet fever (scarlatina) is caused by infection with group A streptococci that produce an erythrogenic toxin. The disease resembles a classical streptococcal pharyngitis, with red tongue (strawberry tongue). There is also a diffuse redness of the skin. The erythema will disappear by pressure. A typical perioral pallor is described. Pastia's lines are dark red lines in skin folds. After the acute phase desquamation will occur. Acute rheumatic fever is a serious complication. Kawasaki syndrome is an important differential diagnosis.
- Bartonellosis initially causes a haemolytic anaemia with fever. This can be followed by nodular or verrugous skin lesions (verruga peruviana).
- Meningococcal septicaemia is a medical emergency. Purpural skin lesions are caused by massive intravascular coagulation (DIC) due to infection with Neisseria meningitidis. Shock and multi-organ failure can rapidly develop. There is a risk of complications with gangrene and destruction of the adrenal glands (Waterhouse-Friderichsen syndrome).
- Chronic gonococcaemia (Neisseria gonorrhoeae) causes intermittent fever, arthritis of the large joints and recurrent skin lesions on the hands, forearms, calves and feet. The petechiae are usually isolated, though they sometimes occur in small groups. There is a central vesicle (blister), surrounded by a red halo. This lesion develops into a haemorrhagic pustule and subsequently heals.
- Subacute bacterial endocarditis can cause petechiae. These are frequent in the nailbed. Osler noduli, Roth spots, a cardiac murmur, haematuria and Janeway lesions may be present. Blood cultures are extremely important. Echocardiography (preferably transoesophageal) should be carried out to detect valve lesions.
- Leptospirosis can occasionally (10%) be accompanied by cutaneous rash, e.g. on the calves (Fort Bragg fever). In typical cases other clinical data (fever, icterus, kidney infection, "aseptic" meningitis, red conjunctivae, tendency to bleeding) will suggest the diagnosis.
- Acute rheumatic fever may be accompanied by erythema marginatum. This is however a rare clinical sign. Erythema marginatum is transient and is considered one of the major Jones’ criteria for the diagnosis of acute rheumatic fever. The lesions are usually very short-lived, but usually reappear on the torso and proximal parts of the limbs. The other major criteria are carditis, arthritis, chorea and subcutaneous noduli. All these symptoms do not occur at the same time.
- Rat bite fever. This term covers 2 different diseases.
- Infection with Streptobacillus moniliformis, a pleomorphic Gram-negative bacillus, can follow after an infected rat or mouse bite or after drinking unpasteurised infected milk (Haverhill fever). After healing of the initial bite wound an abrupt "viral" syndrome occurs, with fever, headache, vomiting and muscle and joint pain (arthritis). A morbilliform petechial rash develops on hands and feet. There is no lymphadenopathy in Haverhill fever. The history and bacterial culture will guide the diagnosis.
- Sodoku is an infection caused by Spirillum minus, a Gram-negative, short, spiral-shaped organism. Lymphangitis, lymphadenopathy, recurrent fever and a recurrent roseola-urticarial rash follow. Sodoku does not lead to arthritis. It has not yet been possible to culture the organism in vitro. There is a high risk of complications involving endocarditis. Treatment is with penicillin or tetracycline.
- Cutaneous anthrax When someone comes into contact with animal fur or hides contaminated with anthrax bacteria, an infection of the skin can follow. After a short incubation period, a small spot appears on the skin at the site of infection. This can initially itch somewhat. Vesicles or blisters will usually form around the central lesion. This is followed by a central ulceration that nevertheless develops painlessly. The ulcer is dry (no pus formation) and there is often a black scab (Greek: "anthrax" = charcoal). Red oedema can occur around the lesion. Regional lymphadenopathy and moderate fever can occur. There is no peripheral leucocytosis. The skin lesion heals slowly. Sometimes the infection will spread, with generalised anthrax as a consequence.
- Pseudomonas aeruginosa septicaemia is accompanied in 13-39% of cases by various cutaneous abnormalities (petechiae, vesicular lesions, nodules, erythema, gangrene = ecthyma gangrenosum).
- Brucellosis. This disease is only rarely accompanied by cutaneous abnormalities (maculopapular rash, erythematous lesions). Persistent fatigue, recurrent fever, neurological problems, bone pain, lymphadenopathy and splenomegaly can occur. Serology and various cultures are necessary for the diagnosis.
- Mycoplasma pneumoniae infection is, in addition to respiratory abnormalities, sometimes accompanied by erythema multiforma.
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A problem that occurs during or after a trip does not necessarily need to have a causal connection with that trip.
- Dengue is probably the most frequent arbovirosis. The disease is often associated with a fine, maculopapular skin rash that disappears when pressure is applied. This is different from the petechiae and ecchymoses that can occur with haemorrhagic dengue.
- Mononucleosis infectiosa is frequently associated with a maculopapular rash. This can be triggered by administration of amoxycillin. Lymphadenopathy, sore throat, mild splenomegaly and abnormal lymphocytes in a thin blood smear early in the infection are suggestive for the diagnosis.
- Coxsackie viruses and other enteroviruses can likewiss cause fever and cutaneous rash. The mouth is also affected in hand-foot-mouth disease (most often caused by Coxsackie A16). The enanthema is vesicular or ulcerative. In 75% of the patients mildly painful vesicular or papulovesicular lesions occur on the palms of the hands and on the soles of the feet.
- Erythema infectiosum (fifth disease) is caused by parvovirus B19. The rash usually starts on the cheeks ("slapped cheeks disease"). It is a cosmopolitan self-limiting disease that mainly affects children. Severe haematological complications (bone marrow aplastic crisis) can occur in sickle cell patients.
- Roseola infantum or exanthema subitum (sixth disease, herpes virus 6) is a viral disease of young children. The rubelliform rash appears whan the fever abates and disappears after the third or fourth day. There is a leukopenia with relative lymphocytosis. Only symptomatic therapy is necessary.
- Measles and rubella, thanks to vaccination, have become very rare. The general symptoms of rubella are limited and post-auricular and suboccipital lymphadenopathy often occur. In the early phase of measles Koplik spots may be present in the mouth. The general symptoms in measles are much more serious than in rubella. Corneal lesions frequently occur in patients with measles in developing countries. Desquamation follows after the acute phase. In cases of malnutrition the mortality of measles is considerable.
- Varicella is quite frequenly seen in children and in non-immune adult tourists. Varicella is caused by a first infection with the varicella zoster virus. The cutaneous rash is initially maculopapular, but quickly becomes typically vesicular and finally gives rise to scabs. The lesions are found in various stages (in contrast to the now eradicated variola major). Lesions also occur on the oral mucosa. Disseminated herpes simplex, monkeypox (very rare) and rickettsial pox can resemble this disease.
- Hepatitis B is occasionally complicated in children by an acute non-pruritic cutaneous rash that disappears spontaneously after 2 to 8 weeks (Gianotti-Crosti-syndrome or acrodermatitis papulosa eruptiva infantilis). The preferred location is on cheeks, buttocks and extremities (not on flexor side of elbows and knees). There are usually swollen lymph nodes. Gianotti and Crosti also described a cutaneous rash that can occur after infections with various other viruses (Coxsackie A 16, parainfluenza B, etc) or after vaccination (poliomyelitis, BCG, tetanus). An acute and slightly pruritic symmetrical exanthema consisting of oedematous, papular or papulovesicular lesions can occur on cheeks, extremities, palms of the hands and soles of the feet, as well as on the torso and on the flexor sides of elbows and knees. There is no enanthema.
- Ebola or Marburg virus. Patients infected with Marburg or Ebola virus exhibit sudden fever, severe headache and muscle pain, malaise, conjunctivitis, occasionally a papular rash, dysphagia, bloody diarrhoea followed by diffuse haemorrhages (especially the mucosae), delirium, shock and ARDS (acute respiratory distress syndrome). Only 5% of the patients exhibit jaundice. In addition to a functional blood platelet disorder there is always thrombocytopenia. Initially there is lymphocytopenia with acute immunosuppression, followed later by neutrophilia. Histologically there are necrotic foci in various organs (testes, kidneys, liver).
- Monkeypox. Monkeypox is a very rare infectious disease, caused by an orthopox virus, morphologically identical to variola. Transmission can occur through contact with infected monkeys or other infected animals (e.g. giant rats, prairy dogs). Secondary cases can occur, though spread from person to person does not generally occur very frequently. Individuals vaccinated against variola are also protected against monkeypox. An incubation of 5-17 days is followed by an influenza-like syndrome. Approximately 2-3 days after appearance of this syndrome a papular skin rash appears, progressing to pustular lesions (including palms of hands and soles of feet). The pustules then often exhibit a central depression. Scab formation occurs and after 10 days these lesions may show a small scar. Substantial lymphadenopathy can occur. Treatment is symptomatic. Cidofovir may be active against this virus. This medicament can be administered intravenously.
- Cowpox: Cowpox is rare and used to occur only in Europe and Russia. The infection occurs in small mammals, cats and mice, and can sometimes appear in large animals, such as cattle and elephants. Humans can also be infected. The majority of cases exhibit vesiculopustular lesions on hands or face. The lesions ulcerate and subsequently develop a black crust. Differentiation from anthrax, mycosis, rickettsial chancre and tularaemia is necessary. Cowpox is caused by an orthopox virus and is related to variola and vaccinia virus. It is thought that infection occurs by direct contact with an infected animal such as a cat or a milking cow with lesions on her udder. The infection almost always remains localised at the site of inoculation. Rarely, there is dissemination via the lymphatics. Disseminated cowpox is extremely rare, but does exist. Spontaneous recovery is the rule with only a small residual scar as a consequence. Of three patients who have had severe infection, there were two with atopic eczema and a third had high fever for which he received steroids.
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- Trypanids
are transient erythemas with indefinite outline that occur in West African trypanosomiasis (Trypanosoma brucei gambiense). The lesions can occur anywhere, but are noticed most frequently on the torso. They can be large (more than 10 cm in diameter) and are triggered by local warmth. Oedema will also occasionally be seen on the face. Fever, splenomegaly and enlarged lymph nodes in the neck suggest the diagnosis. Serology and detection of trypanosomes are essential.
- Various deep mycoses, such as histoplasmosis, cryptococcosis and Penicillium marneffei infection (in AIDS patients in Southeast Asia) can cause fever and skin lesions (pustular, ulcers, erythema nodosum lesions).
Other cosmopolitan diseases to be considered in the differential diagnosis:
- Still’s disease (juvenile rheumatoid arthritis) is characterised by fever, rash, iritis, splenomegaly and generalised lymphadenopathy. Arthralgia (joint pains) and muscle pain are frequent. Arthritis especially affects the larger joints, but might not occur at all. There is leucocytosis. Pleuritis and pericarditis can occur.
- Side effects of medication, such as in erythema multiforma and Stevens-Johnson syndrome, can occur with tetracyclines, sulphonamides, etc. Certain medicinal side effects occur more frequently in AIDS patients (e.g. with thiosemicarbazone, cotrimoxazole). Amoxycillin can trigger or aggravate mononucleosis rash.
- Kawasaki syndrome is a disease of unknown origin. In addition to fever and a morbilliform or scarlatiniform erythema, lesions of the mucosae (stomatitis and non-purulent conjunctivitis, leading to red eyes), a red strawberry tongue and red, dry lips also occurs. There is often cervical lymphadenopathy (mucocutaneous lymph node syndrome). Aseptic meningitis can occur, with mononuclear cells in the cerebrospinal fluid. Cough, diarrhoea, abdominal pain and vomiting occur. There is leucocytosis, thrombocytosis and proteinuria. Desquamation of the hands and feet occurs around days 10-18. There is a risk of complications with coronary aneurysms in 1-2%.
- Toxic shock syndrome can be caused by toxins of certain Staphylococcus aureus strains. The same bacteria can cause a very severe exfoliative dermatitis: the so-called Ritter syndrome or SSSS (Staphylococcal scalded skin syndrome).
- Vasculitis (e.g. leucocytoclastic [hypersensitivity] vasculitis, granulomatous vasculitis, giant cell vasculitis) can be caused by numerous diseases. Cutaneous rash can assume various forms. Henoch-Schönlein purpura is characterised by a maculopapular skin rash (palpable purpura), especially on the calves, buttocks and the lower abdomen. Recurring abdominal pain and joint pain are present. There is a risk of kidney involvement. The disease is related to IgA nephropathy (Berger’s disease).
- Sweet's syndrome is characterised by fever, painful red infiltrated plaques on the face and the extremities, especially the anterior and extensor parts, as well as on the upper part of the torso and the neck. The lesions can have a clear centre. There is neutrophilia, infiltration of the skin with polymorphonuclear cells, arthritis and ocular abnormalities (episcleritis and conjunctivitis).
