Volume 20, Number of Article: 383 (2019)
Fever Fever with renal syndrome (HFRS) is an acute disease caused by infection with hantavirus and is clinically characterized by fever, various manifestations of bleeding and while kidney and liver dysfunction. Although many cases of HFRS have been reported cases in children is rarely explained. Here, we report two cases of atypical HFRS in children without typical manifestations and clinical typical disease progression.
Patient 1 was a 11-year girl who attended our clinic for fever accompanies acute renal failure, proteinuria and decreased levels of complement 3 (C3) and thrombocytopenia without bleeding manifestations, first suspected acute glomerulonephritis, especially lupus nephritis. Patient 2 misdiagnosed as encephalitis at a local hospital because of fever and headache for 4 days. With increased liver transaminases, proteinuria and normal cerebrospinal fluid examination, HFRS was considered. Both of the two cases is supported and confirmed by serology for hantavirus.
The clinical manifestations of HFRS in children are often presented atypically and lighter than adults. Accompanying fever with thrombocytopenia may lead to the diagnosis of suspected HFRS.
HFRS is a zoonosis caused by a virus belonging to the genus hantavirus , which is common among European and Asian countries . It usually presents itself with a triad of fever, bleeding, and acute kidney injury . The disease can manifest itself in five distinct stages characterized by fever, hypotension, oliguria, diuresis and recovery. While the majority of reported cases have been reported in adults [,], children with this disease may have atypical presentations that lead to delayed or missed diagnosis. We here report two children with HFRS, which both delayed diagnosis due to atypical presentation.
A 11-year girl from a rural village to attend our clinic with a history of fever and cough since the six days before. She also complained of muscle weakness and fatigue, and have a decreased urine output and swollen eyes. On physical examination found with mild eyelid and facial edema, facial blushing, mouth ulcers, throat congestion and bilateral pain spine angle. Family history is important for fathers who are recovering from acute kidney injury with unknown etiology 1 year ago.
stable vital signs (BP 96/80 mm Hg, P 106 / min, R 24 / min) and laboratory investigations are described in Table. In short, he got leukocytosis (20.0 × 109 / L, with 64% neutrophils), normal hemoglobin and thrombocytopenia (66 × 109 / L) indicated in routine blood analysis. He got elevated liver transaminases (ALT 228 U / L, AST 235 U / L) and lactate dehydrogenase (764 U / L). In addition, he is blood urea nitrogen and creatinine were 13.32 mmol / L and 104 umol / L respectively, which increased from the usual, and eGFR declined to 64 ml / min. Her albumin (33.7 g / L) and total calcium (1.93 mmol / L) both declined. Routine urine analysis showed proteinuria (3+) and hematuria (2+) with normal RBC numbers in HPF. Renal ultrasonography showed swelling of the kidneys, increased echogenicity and reduce differentiation corticomedullary without urinary lithiasis.
On this basis, it seems like some sort of acute glomerulonephritis obtained after infection. In order to identify the diagnosis, she was admitted to our department. When she was a young girl with a fever, mouth ulcers, thrombocytopenia, proteinuria, hematuria, and especially with decreased levels of C3 were found on the second day after hospitalization, systemic lupus erythematosus (SLE) is taken into consideration first. In addition, her father had fallen into renal failure before, which is provided Alport Syndrome as other speculation. Indexes are other abnormal ferritin raised, combined with changes in routine blood analysis, which makes the bone marrow puncture necessary. Because most benign prognosis of post-infectious glomerulonephritis, a kidney biopsy is not necessary in most cases. However, he quantity of urine protein was 1.24 g / 24 hours, which is rather high for children, a kidney biopsy is under consideration. Titer Mycoplasma pneumoniae (MP) antibody increased to 1:80. MP infection also can cause lung injury, such as liver function disorders and nephritis. Along with fever, he had nausea and vomiting while on the third day. Antibiotics and supportive treatment given to him. Noting the diseases mentioned earlier, we will give her the type of invasive testing. Fortunately, the index gradually recovered to normal after symptomatic treatment, are shown in the Table. On the fifth day, he was no longer a fever. On day six serum found positive for Hantaan virus IgM antibodies using IgM capture ELISA method.
When we repeat history regarding the possibility of exposure to rodents, the family stated that there was a lot of activity of rodents and patients diagnosed as dengue epidemic disease in their homes. During the evolution of the disease, stage of fever and oliguria stage appear at the same time, and diuresis stage appears on the 5th day without hypotension. He recovered well with the rest of supportive therapy without complications.
A girl 13 years was transferred from a local hospital to our department with a diagnosis of encephalitis because of fever and headache for 4 days. She also complained of abdominal pain and orbital. After the presentation, he was normal vital signs (BP 110/70 mmHg, P 100 / min, R 24 / min) and a physical examination including blushing when fever, pale face and eyelid conjunctiva, throat congestion, splenomegaly (spleen is located in the arch subcostal 2 cm) and a negative examination of the nervous system
cerebrospinal fluid examination is taken in a normal clinic (proteins 0.24 g / L, glucose of 6.38 mmol / L, chlorine 121.7 mmol / L, Pan reaction :, negative, WBC 7 × 106 / L, RBC 0 × 106 / L). Routine blood analysis in clinics showed leukocytes with a left shift (5.60 × 109 / L, with 89% neutrophils), mild anemia (HGB 97 g / L) and the normal quantity of platelets (172 × 109 / L), which declined to 104 × 109 / L for the next day. liver transaminase (ALT 143 U / L, AST 96 U / L) and lactate dehydrogenases (638 U / L) both increased. Urinalysis showed proteinuria (3+), while in both blood urea nitrogen and creatinine to normal. Renal imaging also showed kidney swelling (Left: 125 mm x 59 mm; Right: 124 mm x 57 mm; normal range: Left: (93.2 to 105.2) mm × (47.6 to 54.6) mm; right: (84.1 to 94.9) mm × (44.7 to 51.9) mm) and poor corticomedullary differentiation. In addition, ferritin was 444.6 mg / L were removed and heteromorphic lymphocytes (17%) seen on blood smear examination. MP antibody titers increased to 1:80. Detailed laboratory tests described in the table.
The patient presented headache and fever in the autumn, which could easily cause encephalitis pediatrician to take into consideration first. However, with normal cerebrospinal fluid examination in the clinic and the negative examination nervous system in our department, it is ambiguous to make the diagnosis of encephalitis. Because of mild anemia and thrombocytopenia, accompanying with increased ferritin and heteromorphic lymphocytes, we must decide whether or not to perform a bone marrow puncture. In addition, the damage to the hematologic system accompanied by proteinuria occurred in a young girl, we should also pay attention to the identification of SLE. As he complained of pain orbital, HFRS also considered. Despite the possibility, consultation of the department of infectious diseases do not consider HFRS at first.
HFRS then backed up and confirmed by serologic testing him for Hantaan virus on day 3, which was positive. Then he was transferred to the department of infectious diseases for treatment, including antiviral drugs and supportive treatment. During the evolution of the disease, the stage of diuresis appears on the 7th day without stage oliguria and hypotension. Although he was discharged hospital from another department, he is under follow-up by a pediatrician. After receiving supportive therapy, he also recovered.
HFRS is an acute disease caused by Hantavirus in the family Bunyaviridae. This is the kind of zoonoses. Human infection by different viruses present distinct clinical severity. The most common species found in Western-Europe is the Puumala virus , which is usually caused milder forms of HFRS. Especially, infections among children is much lighter than adults . While in Asia, especially in China, Hantaan virus (HTNV) and Seoul virus (SEOV) is a common species [,], which often causes a more severe form of HFRS, It should be noted that the new European hantavirus, viral Sochi, have been discovered that cause severe program Hantavirus disease with high mortality rates . Besides HFRS, hantavirus can cause hantavirus cardiopulmonary syndrome (HCP) or hantavirus pulmonary syndrome (HPS).
Human infection occurs primarily through via virus-containing, rodent excretions aerosols such as urine, feces, or saliva . It is more common among the rural population where the common rat infestations. Rodents act as a natural habours of hantavirus and can transmit the disease through direct inoculation with a bite. Victims can also be infected through contact with contaminated dropplings mice with the virus . Although both our patients denied bitten by rats, they may have contacted dropplings contaminated without notice. In addition, the father of our first patients have similar clinical presentations last year supporting the postulation that they both may have been exposed to hantavirus in the same neighborhood.
constellation HFRS disease include fever, various hemorrhagic manifestations and temporary liver / kidney function disorder . This usually takes place in five distinct stages, including fever, hypotension, oliguria, diuresis and recovery . The presence of endothelial damage, as evidenced by capillary dilation and leakage, considered characteristic of hantavirus infection . Although the exact pathomechanisms unclear, puzzles clinically indicated cytokine production, kallikrein-kinin and complement activation, and increased levels of circulating immune complexes suggest an important role of the immune response to infection.
hantavirus infection despite a global health issue , approximately 90% of the reported cases were from China . Although childhood infection is not common among the cases reported, this phenomenon may be due to lack of diagnosis, as the clinical manifestations of HFRS in children can be atypical . Meanwhile, it was reported that the clinical impression of HFRS milder in children than in adults . In their study, they conclude three different aspects. First, in the aspects of clinical symptoms, adults usually have arthralgia, muscle pain, and visual disturbances, transient abdominal pain and vomiting occurred more often in children than in adults. Second, in the aspect of physical signs, transient hypertension is more common in children. Third, in laboratory tests almost all adults have significant leukocytosis, whereas in children the most common laboratory findings are thrombocytopenia. However, recent analysis shows a different view . Despite certain differences between the symptoms of acute kidney injury (AKI) and thrombocytopenia occurred at the same frequency and severity in children and adults. Other studies have indicated that the presence of thrombocytopenia highly sensitive and specific for detecting patients with hantavirus infection . Platelets also a predictor and marker of disease severity and development [,].
In childhood, hantavirus infection is not a common etiology of acute kidney injury. HFRS diagnosis is based on clinical manifestations, epidemiological data and laboratory tests. However, in cases with mild or atypical clinical symptoms, it is difficult to diagnosis based solely on clinical symptoms or signs. In this situation, laboratory tests turn out to be important. The most common serological tests are indirect IgM and IgG ELISA and IgM capture ELISA [,]. In addition, the hantavirus infection can be confirmed by detection of hantavirus genome in blood or serum samples by RT-PCR. Consider the economy, we adopted the method of IgM capture ELISA in our midst. Both of these two patients were confirmed by a positive test for the virus Hantaan IgM antibodies. However, it often takes a long time to get the results of serological tests to support a presumptive diagnosis. When we reviewed the course of diagnosis and treatment, we tired to work out that the symptoms leading to the diagnosis is suspected. In patient 1, in addition to fever, he showed acute liver and kidney injury associated with thrombocytopenia and low levels of C3, but he did not have clinical features of bleeding, nor did he reveal the physical signs of any hypertension. In addition, both fever and thrombocytopenia can occur either blood disease or autoimmune disease, which makes us almost gave him a bone marrow puncture and kidney biopsyy. Also he was not served in a typical five different phases. Therefore, its hantavirus infection was not confirmed until the results of serological later confirmed. Delay in the serological tests led to a dilemma in the initial examination and treatment. Similarly, in patient 2, the presentation of fever with severe headache has also been given a diagnosis of HFRS clinical challenges during its initial course. Although there is nausea and vomiting in patients 1 and 2 abdominal pain in patients, these symptoms are not specificity. In addition, the hybrid infection often occurs in children, such as MP infection in two patients, who can make us confused. Former literature and presentation of our case, accompanying fever with thrombocytopenia in patients with suspected diagnosis may cause HFRS. It gave us a reminder to consider HFRS and distinguish from other diseases.
The decrease while the level of C3 in Patients 1 may support that immune mechanisms play an important role in the pathogenesis of HFRS. their platelet counts recovered immediately presented that they were under only mild disease also. There splenomegaly, anemia and heteromorphic lymphocytes in patients 2, which may be due to inflammation of the spleen. Inflammation in the spleen were reported on hantavirus infection in the host . However, that can not be identified, as we did not do a bone marrow puncture and further examination. It is a limitation that we did not do a kidney biopsy to them, so we can not recognize HFRS renal pathology. Because they have a full recovery, the benefits for patients who did not undergo invasive testing.
In the case of hantavirus infection is no specific treatment. Hantavirus infection is generally the primary treatment mainly supportive. Renal function recovered fully within a few days in most cases. Hemodialysis, oxygen therapy and shock therapy is sometimes necessary. However, when it comes to the condition of the deadly hantavirus infection, there is an increasing demand to develop specific therapies. Under the pathogenesis is known, drugs known to affect an increase in capillary permeability, such as kinases, angiopoietin 1 and sphingosine 1phosphate in clinical trials . Fortunately, both our patients had mild manifestations and recover fully without residual damage after supportive therapy. What needs to be explained is that our 2 patients received antiviral drugs (ribavirin) in the department of infectious diseases. Controversy has arisen in whether or not the use of ribavirin in the treatment of HFRS. A previous trial, where prospective, double-blind, methods simultaneously, placebo-controlled trial was used to observe the effects of intravenous ribavirin therapy HFRS in China, reported that both morbidity and mortality significantly decreased . However, a recent trial for the treatment of HFRS in Russia showed that intravenous ribavirin did not alter the kinetics of viral load . Consider the side effects of the use of ribavirin in children, we do not suggest that children treated with ribavirin for HFRS. The best defense would be to prevent serious infections from occurring. Since there is no FDA-approved vaccine or treatment for hantavirus disease is present , it is urgent to develop a vaccine in the post-exposure prophylaxis.
Our patient illustrates how HFRS in children is a clinical entity with multiple manifestations, and a high index of suspicion is very important in making the correct diagnosis. When facing unexplaned accompanying fever with thrombocytopenia, pediatricians should HFRS into consideration. serological tests for the diagnosis should be adopted in time. Early acknowledge can avoid unnecessary invasive testing and treatment delays.
dataset used is analyzed for the current study is available from the corresponding author on a reasonable request.
acute kidney injury
estimated glomerular filtration rate
Enzyme-linked immuno sorbent assay
food and Drug Administration
hantavirus syndrome, cardiopulmonary
fever fever with renal syndrome
hantavirus syndrome, pulmonary
virus Hantaan < p> Mycoplasma pneumoniae
reverse transcription – PCR
systemic lupus erythematosus
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We are grateful to the patients, families and authors who participated in this study they .. At the same time, we are grateful to Professor Keithk Lau of University of Hong Kong to revise the language of the article.
There is no funding.
LZ collect clinical information and wrote the manuscript. YZ, BCS and Lyz support data collection, data interpretation. SMM was involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Written informed consent was obtained from parents of both the patient for publication of this case report. A copy of the written consent is available for review by the Editor of this journal.
The authors declare that they have no competing interests.
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Zhang, L., Ma, T., Zhang, Y. et al. Analysis of diagnosed cases of hemorrhagic fever with renal syndrome in children: two cases and review of the literature.
BMC Nephrol 20, 383 (2019). https://doi.org/10.1186/s12882-019-1562-0
Received: March 17, 2019
Received: 20 September 2019
Published: October 23, 2019
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