Severe Thrombocytopenia in a Child With Typhoid Fever: A Case Report

Mohammed Al Reesi; Glenn Stephens; Brendan McMullan

Disclosures

J Med Case Reports. 2016;10(333) 

In This Article

Discussion

Typhoid or "enteric" fever is a systemic infection caused by Salmonella enterica subsp. enterica serovar Typhi and occasionally Salmonella Paratyphi. It is characterized by severe systemic illness, often presenting with features of fever, constipation, and abdominal pain. Its incidence in endemic countries can be as high as 540 cases per 100,000 population, making it a public health challenge.[1] In an Australian setting, it particularly affects returned travelers from the Asian subcontinent.[2]

Important differential diagnoses of typhoid fever in a returned traveler from South and Southeast Asia include dengue fever and malaria. In addition, acute murine typhus can have similar presentation to typhoid fever. It is common, yet underdiagnosed, in travelers from this region. Thompson et al.[3] found serologic evidence of acute murine typhus in 17% of patients who presented with undifferentiated febrile illnesses at a tertiary referral hospital in Nepal. All patients had sterile blood cultures with no cases of murine typhus found among those with confirmed enteric fever.[3] We did not investigate our patient for murine typhus or other rickettsial infection because typhoid fever was confirmed promptly on day 2 of his admission.

Thrombocytopenia is an important finding in the assessment of returned febrile travelers. It is defined as a platelet count below the lower limit of normal (i.e., <150 × 109/L). It is further subdivided into mild (100–150 × 109/L), moderate (50–99 × 109/L), and severe thrombocytopenia (<50 × 109/L). In a study conducted in an outpatient clinic in Germany, 3.8% of returned travelers had thrombocytopenia.[4] Typhoid/paratyphoid fever was responsible for 14% of the cases, ranking fifth after malaria, acute human immunodeficiency virus (HIV) infection, dengue fever, and Epstein-Barr virus (EBV) infectious mononucleosis. The most frequent travel destination in the study was Asia (42%).[4] Thrombocytopenia is well reported in patients with typhoid fever. Malik[1] reported an incidence of 26% in Malaysian children with typhoid fever and Pohan[5] found it in 61.5% of cases in one study of adults. Despite this, the pathophysiology of thrombocytopenia and its clinical course in typhoid fever are not well understood. Proposed mechanisms of the hematological manifestations of typhoid fever, including thrombocytopenia, include bone marrow suppression, peripheral destruction by the reticuloendothelial system, autoimmune-induced destruction, and Salmonella endotoxin-induced thrombocytopenia.[5,6] Bone marrow examination was not performed in our patient but we note he had abnormalities in three hematological cell lines, suggesting possible bone marrow suppression.

Factors that might contribute to the severity of typhoid fever include the duration of illness before therapy, the inoculum size, the immune status of the patient, and the previous vaccination against typhoid fever.[7] Our patient had been unwell for several weeks before presentation and thus the inoculum size at the time of commencing treatment could have been relatively high. He had no known or suspected immunodeficiency, but had not received a typhoid vaccination prior to travel to Bangladesh, which could have prevented this illness. The duration of illness and fever in patients with typhoid strains resistant to ampicillin, chloramphenicol, and trimethoprim can be more prolonged despite receiving antibiotics to which strains are susceptible.[8] Salmonella Typhi haplotype H58 predominates in many parts of Southeast Asia and is responsible for most multidrug resistance.[9] We did not perform genetic typing for our isolate, but its resistance to ampicillin, chloramphenicol, and trimethoprim, with decreased susceptibility to ciprofloxacin, suggests it may have been this haplotype.

In addition to splenomegaly and leukopenia, thrombocytopenia is considered a sign of severe disease in typhoid fever with a higher risk for development of complications. Thrombocytopenia usually develops during the course of the illness, but it can be a presenting feature of typhoid fever, as in this case. Severe complications of typhoid include intestinal perforation, intracranial hemorrhage, and multi-organ failure.[6,7] Among 102 children with typhoid fever in one study, 33% developed complications, most commonly anicteric hepatitis and bone marrow suppression, but also paralytic ileus, myocarditis, psychosis, cholecystitis, osteomyelitis, peritonitis, and pneumonia. The rate of any complications among those with thrombocytopenia was 54%.[1] Our patient had anicteric hepatitis, hypoalbuminemia with ascites, and thrombocytopenia, but he remained alert and oriented without any clinical evidence of intracranial hemorrhage despite a platelet nadir of 16 × 109/L on day 5 of admission. He also did not have any clinical evidence of intestinal perforation and his renal function remained normal throughout his admission. Considering our patient's pancytopenia, we considered the possibility of infection-associated hemophagocytic syndrome as a complication of his typhoid fever, because this has been previously reported.[10] Given that he was slowly improving clinically, we decided to observe him closely without performing additional invasive tests, such as bone marrow examination. Further investigation, including consideration of hemophagocytic syndrome, would have been required if he had failed to improve.

Because the risk of hemorrhage is increased when the platelet count falls below 20 × 109/L, this level was traditionally considered the threshold for prophylactic platelet transfusion. Later prospective studies have proved that lowering this trigger to 10 × 109/L in stable patients with cancer or blood disorders is still safe. However, platelet count should not be the only indicator for deciding transfusions. Other important elements that indicate the patient is at increased risk of bleeding, and thus likely to have an increased need for platelet transfusion, include raised body temperature, sepsis, and rapid decrease in platelet count. Like most blood products, platelet transfusions are not free of adverse effects. These include blood-borne infections, although now rare owing to good screening; bacterial contamination; febrile transfusion reactions; transfusion-related acute lung injury; and anaphylactic reactions.[11]

There are no studies or guidelines addressing the management of thrombocytopenia in typhoid fever. This poses a challenge for clinicians, especially when faced with severe thrombocytopenia, as in this case. Some case reports have described platelet normalization shortly after starting antibiotic therapy without a need for platelet transfusion.[12,13] In one case, however, the platelet count fell from 154 × 109/L to 14 × 109/L despite antibiotic therapy, and this was associated with multi-organ failure; plasma exchange was given to correct the thrombocytopenia and other abnormalities.[7] One adult patient died from severe hemolytic uremic syndrome attributed to Salmonella Typhi, with failure to respond to a platelet transfusion given along with a blood transfusion and plasmapheresis.[14] Our patient had a relatively slow recovery with fever and hepatitis persisting for 2 weeks, despite appropriate antibiotic therapy, and a slow return to normalization of platelet count on day 11. However, he avoided a platelet transfusion and was well at last follow-up.

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