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Rhabdomyolysis and Influenza A (H3N2) infection--a case report/ Rabdomioliza i influenza a (H3N2) infekcija--prikaz slucaja.


Influenza causes respiratory tract diseases with acute respiratory distress syndrome (ARDS) as the leading and most severe life threatening complication. In terms of early diagnosis, extrapulmonary complications are less common, but clinically a significant problem [1]. In the territory of Vojvodina, influenza occurs in epidemic forms, usually in the winter months. The most common cause is the virus Influenza A. In the season 2014/2015, the dominant type was A/H3N2. Pulmonary complications were the most common complications, and also the most common cause of death [2, 3]. However, we are witnessing the appearance of other rare and often unrecognized, life threatening complications.

Rhabdomyolysis (RM) is the destruction of skeletal muscle followed by the release of intracellular myofibrils into the bloodstream and extracellular fluid. Clinical manifestations vary, from asymptomatic to life threatening conditions, such as acute renal failure and disseminated intravascular coagulation [4]. Although myositis is the most common symptom of the flu syndrome, the development of RM is rare, and it is more likely to occur in individuals with a genetic predisposition.

The aim of this paper is to highlight RM as a potentially life threatening complication of influenza.

Case Report

At the beginning of January 2015, a seventeen year old girl presented with Influenza syndrome (dry cough, elevated body temperature up to 38[degrees]C). She was under regular medical supervision due to asthma therapy in the past two years (budesonide and formoterol as needed). Five days after the onset, bronchopneumonia was detected by auscultation, and cefpodoxime (200 mg per 12 hours) was initiated. The respiratory symptoms have resolved, but at the same time muscle weakness with intense pain and inability to move started. The patient presented with dark discoloration of the urine, and was admitted to a regional hospital in the second week of February with the diagnosis of suspected infectious myositis.

On admission, the patient was afebrile, hypotensive, tachycardic, cyanotic with generalized skeletal muscle pain, and with paresis of all extremities and hyporeflexia. The laboratory findings showed the following: C-reactive protein (CRP) 21.7 (below 5 mg/l), aspartate aminotransferase (AST) 572 (below 37 U/l), alanine transaminase (ALT) 130 (below 40 U/l), lactate dehydrogenase (LDH) 1684 (460 U/L and creatine phosphokinase (CPK) 19344 (below 171 U/l), and after basic diagnostic procedures were performed, intravenous hydration and antibiotic therapy (ceftriaxone, amikacin) were initiated. Despite the administered therapy, the laboratory findings got worse: an increase of leukocytes, anemia, thrombocytopenia, hypoalbuminemia, CPK 176 421 (below 168 U/l), AST 3080 (below 37 U/l), ALT 467 (below 40 U/l), LDH 3209 (below 460 U/l) and after 24 hours the patient was transferred to the Clinic of Infectious Diseases for suspected sepsis and infectious myositis.

Intensive intravenous hydration with mannitol and correction of metabolic acidosis were performed. Immunological tests (anti nuclear antibodies--ANA, anti neurotrophic cytoplasmatic antibody virus--ANCA, anti-double-stranded deoxyribonucleid acid At) were negative. Assessments were done for Adeno, Coxsackie A and B, Influenza A and B, Parainfluenza, Varicella Zoster, Herpes Simplex, Respiratory Syncytial Virus, Epstein Barr Virus, Parvo B19, Cytomegalovirus infections, Mycoplasma pneumonia, Hepatitis B Virus surface antigen (HBsAg), anti Hepatitis C Virus antibody (AntiHCV), which proved negative. However, polymerase chain reaction (PCR) microbiological analysis of the throat swab was Influenza A H3N2 positive. As there was no satisfactory response, corticosteroids (methylprednisolone 120 mg) was initiated, that resulted in moderate clinical and laboratory improvements.

During further treatment at the Clinic of Infectious Diseases the patient was gradually recovering. Electromyoneurography (EMNG) indicated a severe acute polyneuropathy of muscles innervated by perineal nerve and signs of polymyositis. Histopathological examination of the left gastrocnemius confirmed chronic myositis with necrotic neurogenic atrophy. After six weeks of treatment, the patient was discharged recovered, with blood results within reference ranges, with weakness of foot dorsiflexor, tilting of the pelvis to the left during verticalization. Eighteen months later, there were mild sequelae--occasional pain in the muscles of the lower extremities and difficulty doing squats.


Myositis is a well-known manifestation of numerous infectious diseases, viral infections being the most common (Influenza A and B, Coxsackie Virus, Epstein Barr Virus, Herpes Simplex Virus, Parainfluenza, Adenovirus, Echovirus, Human Immunodeficiency Virus (HIV) and Cytomegalovirus (CMV). In general, myositis is not the main symptom and rarely progresses to life threatening RM.

Presented Influenza A virus infection was confirmed by detection with PCR isolation from the pharynx swab and serology test--detection of IgM Influenza A antibodies by the ELISA method. Prolonged duration of viral shedding, unusual for Influenza A virus, can be explained by the application of corticosteroid therapy in the treatment of asthma [5, 6].

Although there are indications of direct viral myotoxic effect (EBV), RM is most often the result of T-cell hyperactivity [7, 8].

A number of exogenous and endogenous factors may accelerate destructive immune response to the muscle tissue [4]. The most common concomitant factors, which may contribute to the development of RM in viral infections, are alcohol abuse and use of certain drugs, which was excluded by toxicological analyses. Cytochrome P450 inhibitors (statins, acetaminophen) are described as the most provoking factors of RM; although the pathogenesis is still not proven, it is believed that they reduce production of adenosine triphosphate (ATP) within the muscle cells which destabilizes the membrane [8]. However, our patient denied taking drugs from this group. Genetic predisposition for the development of RM should also be taken into consideration.

According to recent studies, people with virus induced RM are often carriers of mutations of RYR1 gene that creates defective ryanodine receptor 1 on myocytes, thus creating susceptibility to malignant hyperthermia, which leads to RM. We could not perform genetic analysis, but we considered genetic predisposition unlikely to be the cause of RM due to the long latent period (one month), and absence of high body temperatures (up to 38[degrees]C). A number of metabolic, genetically determined RM can also occur, but they are usually recurrent and occur after intense physical activity, regardless of the infection. The patient regularly practiced folklore and never complained of myalgia, nor reported darker urine color.

Progression of symptoms in terms of difficulty of movement, inability of verticalization and dark urine, immediately pointed to RM, especially when blood results showed five times elevated CPK levels and acidosis, with pathological urine [9]. Myoglobinuria is the last of three classical RM symptoms (nausea, myalgia, dark urine) that appeared. It is present in less than 10% of patients with RM, and most patients do not have weakness or myalgia, but do have systemic manifestations such as tachycardia, fever, nausea and vomiting [3]. Myoglobinuria does not occur without RM, but RM is not a mandatory result in myoglobinuria. It occurs when the threshold of renal filtration from 0.5 to 1.5 mg/dl is exceeded, and it is macroscopically visible only when the quantities reach 100 mg/dl [10]. Myoglobin in the urine of our patients was not determined, since this analysis is not included in the standard diagnostic procedure.

The main complications of RM are acute kidney failure, electrolyte imbalance, especially hyperkalemia which leads to arrhythmia, hypophosphatemia and hypocalcaemia. In order to prevent this, quick and adequate therapy is needed. Intense iv. hydration with saline 300-500 ml/h should be given. Since our patient was hemodynamically stable, these quantities of fluid were not exceeded. Although there is no protocol in the literature to define duration of intense hydration, it is considered that it should be applied until the level of serum CPK decreases to 1000 U/l or less [4]. Alkalization of urine with sodium bicarbonate (NaHC[O.sub.3]) is beneficial in three ways: it reduces precipitation of Tamm-Horsfall protein-myoglobin complex, it inhibits oxidation-reductive process of myoglobin and lipid peroxidase reducing the damage to the tubules, and it reduces vasoconstriction caused by metmyoglobin in acidic environment [11, 12]. It is recommended to apply infusion of one ampoule of NaHC[O.sub.3] (20 ml, 1 ml contains 84 NaHC[O.sub.3]) in one saline bottle or 2-3 ampoules in one 5% glucose bottle at 100 ml/h rate, in order to maintain urine pH above 6.5 preventing acute kidney failure. Hemodialysis is considered in cases with excessive hyperkalemia and metabolic acidosis [13, 14]. Given the small amount of data on the efficacy of corticosteroids in the treatment of RM, and bearing in mind they are used in recurrent RM with chronic myositis of autoimmune etiology, they were not administered during hospitalization in our clinic [15].

Delayed development of RM (one month after the first symptoms) and good therapeutic response to corticosteroids, despite negative immunological test results, may point to autoimmune diseases in the background (dermatomyositis, polymyositis). Biopsy of m. gastrocnemius has been done according to the recommendations -8 weeks after the first symptoms and four weeks after completion of corticosteroid therapy. The result was chronic myositis with necrotic neurogenic atrophy, reactive inflammation with no signs of immune or dystrophy myositis. Considering good recovery and minimal sequelae, with no signs of recurrence, we concluded that RM was caused by Influenza A virus (H3N2).


Complications of Influenza A are a global problem, so it is of crucial importance to take into consideration the range of clinical manifestations, beyond the typical symptoms of respiratory infections. Reports on rhabdomyolysis caused by influenza-A are increasing and given the degree of morbidity and mortality, assessment of patients suspected for the development of rhabdomyolysis should be done carefully, especially those with general weakness and muscle pain.

ARDS            --acute respiratory distress syndrome
RM              --rhabdomyolysis
CRP             --C-reactive protein
AST             --aspartate aminotransferase
LDH             --lactate dehydrogenase
ALT             --alanine transaminase
PCR             --polymerase chain reaction
CPK             --creatine phosphokinase
NaHC[O.sub.3]   --sodium bicarbonate


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[2.] Zarazne bolesti u AP Vojvodini 2015. godina [Communicable diseases in Vojvodina, 2015]. Novi Sad: Institut za javno zdravlje Vojvodine; 2016. Serbian.

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[6.] Fadila MF, Wool KJ. Rhabdomyolysis secondary to influenza a infection: a case report and review of the literature. N Am J Med Sci. 2015;7(3):122-4.

[7.] Hodel C. Myopathy and rhabdomyolysis with lipid-lowering drugs. Toxicol Lett. 2002;128(1-3): 159-68.

[8.] Ruzic M, Fabri M, Pobor M, Jovelic A, Lukac D. Exercise induced rhabdomyolysis. Vojnosanit Pregl. 2009;66(9):754-7.

[9.] Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62-72.

[10.] Lane R, Philps M. Rhabdomyolysis has many causes, including statins, and may be fatal. BMJ. 2003;327(7407):115-6.

[11.] Heyman SN, Greenbaum R, Shina A, Rosen S, Brezis M. Myoglobinuric acute renal failure in the rat: a role for acidosis? Exp Nephrol. 1997;5(3):210-6.

[12.] Malik GH. Rhabdomyolysis and myoglobin-induced acute renal failure. Saudi J Kidney Dis Transpl. 1998;9(3):273-84.

[13.] Chatzizisis YS, Misirli G, Hatzitolios AI, Giannoglou GD. The syndrome of rhabdomyolysis: complications and treatment. Eur J Intern Med. 2008;19(8):568-74.

[14.] Antoon JW, Chakraborti C. Corticosteroids in the treatment of alcohol-induced rhabdomyolysis. Mayo Clin Proc. 2011;86(10): 1005-7.

Rad je primljen 27. II 2017.

Recenziran 20. III 2017.

Prihvacen za stampu 29. III 2017.


Anja STOJSIN, Vedrana PETRIC, Grozdana CANAK, Vesna TURKULOV, Sinisa SEVIC and Maja RUZIC

University of Novi Sad, Faculty of Medicine

Clinical Center of Vojvodina

Clinic of Infectious Diseases

Corresponding Author: Dr Anja Stojsin, Klinicki centar Vojvodine, Klinika za infektivne bolesti, 21000 Novi Sad, Hajduk Veljkova 1-7, E-mail:
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Article Details
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Title Annotation:Case report/Prikaz slucaja
Author:Stojsin, Anja; Petric, Vedrana; Canak, Grozdana; Turkulov, Vesna; Sevic, Sinisa; Ruzic, Maja
Publication:Medicinski Pregled
Article Type:Case study
Date:May 1, 2017
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