Rhabdomyolysis and Neurological Manifestation With Progressive Weakness in a Young Adult: A Rare Extrapulmonary Presentation of Mycoplasma Pneumoniae

Mycoplasma pneumoniae (M. pneumoniae) is a common cause of community-acquired pneumonia. It has been associated with many extrapulmonary manifestations that can present even in the absence of pulmonary signs and symptoms. Rhabdomyolysis and central nervous system (CNS) manifestations are rare extrapulmonary manifestations. These are infrequently reported in adults. We present a case of a healthy 32-year-old male who initially presented with signs and symptoms of community-acquired pneumonia and was treated with antibiotics. However, he continued to have generalized malaise, night sweats, diffuse joint pain, and myalgias and was subsequently noted to have rhabdomyolysis with elevated creatine kinase (CK) and myoglobin levels. Rhabdomyolysis was attributed to M. pneumoniae based on the recent history of upper respiratory tract infection and M. pneumoniae immunoglobulin M (IgM) serology positivity along with high M. pneumoniae IgG titer. The other causes of rhabdomyolysis were diligently excluded based on patient history and laboratory and clinical data. This immune-mediated rhabdomyolysis improved with intravenous hydration, doxycycline, and prednisone therapy. However, the patient developed progressive weakness with neuropathy, which required treatment with intravenous immune globulin (IVIG). This case highlights the need to maintain a high index of suspicion for rare extrapulmonary manifestations of mycoplasma infection, which could be life-threatening or cause significant morbidity; and in cases of severe extrapulmonary manifestations, the appropriate use of immunosuppressive/immunomodulatory therapy may lead to a better outcome.


Introduction
Mycoplasma pneumoniae (M. pneumoniae) causes acute respiratory illness, which ranges in severity from mild upper respiratory tract infection to pneumonia. It is associated with an annual incidence rate that amounts to approximately 1% of the United States population. It can affect any age group but is more common in children aged more than five years and young adults aged less than 40 years [1,2]. The incubation period is about two to three weeks, and patients can be completely asymptomatic or present with clinical symptoms of headache, malaise, fever, chills, and cough; 3-10% of infected people can develop pneumonia [3]. An extrapulmonary disease that can include hematological, dermatological, cardiac, gastrointestinal, neurological, and musculoskeletal manifestations can occur in about 5-10% of patients infected with mycoplasma and can appear before, during, after, or in the absence of pulmonary signs [3,4]. Polyarthralgia and myalgia are common musculoskeletal manifestations but rhabdomyolysis is rare; most cases involve pediatric patients and only a handful of cases have been reported in healthy adults [5][6][7][8][9][10][11][12][13][14]. Central nervous system (CNS) manifestations can present as meningitis, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, cranial nerve palsies, or cerebellar ataxia and occur in approximately 0.1% of patients with M. pneumoniae infection [15]. In this report, we present a rare case of rhabdomyolysis followed by neurological manifestation with progressive weakness secondary to M. pneumoniae infection in a young adult.

Case Presentation
A 32-year-old-male with no significant past medical history presented to the emergency room with complaints of chills, cough, shortness of breath, chest congestion, and generalized malaise for two days. He denied fever, chest pain, nausea, vomiting, diarrhea, dysuria, abdominal pain, and any sick contact or travel history. He was not taking any prescribed or over-the-counter medications. Initial vitals revealed a temperature of 98.2 °F, heart rate of 100 beats/minute, blood pressure of 140/85 mmHg, and respiratory rate of 18 breaths/minute with 98% oxygen saturation on room air. Physical examination was significant for reduced breath sounds bilaterally with mild expiratory wheezing. The rest of the physical examination was unremarkable. Initial laboratory workup was significant for a leukocyte count of 22.6 x 10 3 /µl with 83.9% neutrophils; the rest of the laboratory findings were unremarkable (  The chest X-ray revealed a faint infiltrate on the left lung base ( Figure 1).

FIGURE 1: Chest X-ray showing faint infiltrate on the left lung base (arrow)
Additional workup with respiratory pathogen panel with nucleic acid amplification test (NAAT), which includes influenza A, influenza B, parainfluenza, human coronavirus, human metapneumovirus, Bordetella pertussis, Chlamydia pneumoniae, and M. pneumoniae, were negative. Urine Streptococcus and Legionella antigen were negative as well. The patient was hospitalized and treated with albuterol nebulization, intravenous methylprednisolone, and intravenous ceftriaxone, and oral azithromycin. His leukocytosis trended down and procalcitonin remained negative along with blood cultures for 48 hours and he was discharged home on azithromycin, steroid taper, and albuterol inhaler for wheezing as needed.
He followed up with his primary care physician (PCP) after one week of discharge and reported that his cough, chest congestion, and shortness of breath had resolved but stated that he continued to experience excessive fatigue with intermittent subjective fever, night sweats with diffuse joint pain, and myalgia. His vital signs and physical examination were unremarkable. His repeat laboratory workup was significant for persistent leukocytosis of 17.5 x 10 3 /µl, elevated creatine kinase (CK) levels of 2537 U/L, and elevated myoglobin level of 1258 U/L. The rest of the laboratory workup was unremarkable as summarized in Table  1. Additional workup including serum cortisol, thyroid-stimulating hormone (TSH), complements levels (C3, C4, CH50), antinuclear antibodies (ANA), anti-neutrophilic cytoplasmic autoantibody (ANCA), and anticyclic citrullinated peptides (anti-CCP) were unremarkable; however, M. pneumoniae IgM was reactive. He was hospitalized and started on intravenous normal saline at 200 ml/hour and CK levels were monitored closely. Since he had been previously treated with azithromycin, doxycycline was started for positive M. pneumoniae IgM given the possibility of mycoplasma resistance to macrolides. Despite aggressive intravenous hydration and doxycycline, his CK level trended upwards and he continued to have generalized muscle soreness; he was started on prednisone 1 mg/kg dose for immune-mediated rhabdomyolysis. His CK level gradually trended down along with improvement in his myalgia ( Figure 2).

FIGURE 2: Creatine kinase (CK) level trend during hospitalization
He was discharged home on the seventh day of admission with a CK level of 253 U/L with oral prednisone taper.
Within 24 hours of discharge, he started to have bilateral lower extremity weakness and suffered multiple falls at home, and was readmitted the next day. On readmission, his vitals were unremarkable; however, physical examination was significant for quadriparesis with a muscle power of 4/5 ( Table 2), with intact deep tendon reflex, and decreased sensation to pinprick in bilateral lower extremities below his knees and bilateral upper extremity below his elbows.

Grade Characteristics
Grade 5 Muscle contracts normally against full resistance   Table 1, and his CK level was within normal limits. Imaging studies with MRI brain and spine with and without contrast were unremarkable. A lumbar puncture was done, which was also unremarkable ( Table 3).  Lyme disease antibodies, Coccidioides antibodies, Blastomyces antibodies, toxoplasma IgG antibodies, Anaplasma serum antigen, and hepatitis C antibodies were also unremarkable. The patient was continued on oral prednisone 1 mg/kg. However, the next day, he started to have a progressive weakness with decreasing muscle power of 3/5 ( Table 2) in all four extremities along with the progression of numbness with decreased pinprick sensation from lower extremity to the thoracic level of T-10; his deep tendon reflexes were intact. He was started on intravenous immune globulin (IVIG) infusion at 0.4 mg/kg and monitored closely in the ICU. His weakness and numbness gradually improved with IVIG, which was given for five days. He worked with physical and occupational therapy and was able to ambulate with the help of a walker on the day of discharge. He followed up with neurology outpatient and electromyography (EMG) was done after two weeks, which was unremarkable. He recovered completely after a total of six weeks of outpatient physical therapy.

Discussion
Rhabdomyolysis involves the breakdown of skeletal muscles resulting in the release of intracellular components, including myoglobin, CK, and other intracellular electrolytes in circulation. Clinically, it can be asymptomatic or present with myalgia, muscle swelling, muscle tenderness, or passage of tea-colored urine. The diagnosis is usually based on myalgia or urine analysis (UA) that tests positive for blood in the absence of red blood cells on microscopy. Serum CK level greater than five times the upper limit of the normal range is the hallmark of rhabdomyolysis and is sufficient to establish the diagnosis [16]. It is usually managed with aggressive intravenous hydration to prevent myoglobin-induced renal failure, which could develop in about 50% of patients with rhabdomyolysis, along with treatment of the causative factors [4].
Rhabdomyolysis triggered by M. pneumoniae is a rare extrapulmonary manifestation and has been infrequently reported in healthy adults [5][6][7][8][9]. The pathogenesis of rhabdomyolysis is not completely understood and the proposed mechanism includes immune-mediated reaction or direct invasion of affected muscles by the organism [16]. CNS manifestation is another rare extrapulmonary manifestation and occurs in approximately 0.1% of patients with mycoplasma infection [15]. Encephalitis is a common CNS manifestation but can present with meningitis, peripheral neuropathy, Guillain-Barré syndrome, cranial nerve palsies, transverse myelitis, and cerebellar ataxia. The prognosis varies with the type and extent of CNS involvement but can be poor [15].
Diagnosis of mycoplasma infection usually depends on polymerase chain reaction (PCR) gene amplification technique or serological test as the organism is fastidious and difficult to culture. PCR is typically done when it is available but, in most cases, serology for M. pneumoniae IgM is performed. In one study, the overall sensitivity of PCR was 40% compared to 40% and 35% for IgM and IgG/IgM assay respectively [18]. The sensitivity of PCR declines with the passage of time since infection. IgM titer rises earlier than IgG (approximately seven-nine days into infection); the gold standard for serologic diagnosis requires a four-fold rise in IgG titers both during acute infection and during the recovery phase (approximately four weeks later), which is generally impractical. Hence, a single high IgM titer can be used to make a presumptive diagnosis [19].
Antibiotic therapy with macrolides, fluoroquinolones, or tetracyclines is the mainstay of treatment for nonrespiratory mycoplasma presentation. However, the use of immunosuppressive agents or immunomodulatory therapy including glucocorticoids, IVIG, and plasmapheresis is warranted in some extrapulmonary diseases, especially CNS manifestations or severe hematological involvement [4,15]. Macrolide resistance has been increasing in frequency and it has become important to consider macrolide resistance when selecting antibiotic treatment [20].
In our case, rhabdomyolysis was attributed to M. pneumoniae based on the recent history of upper respiratory tract infection and M. pneumoniae IgM serology positivity along with high M. pneumoniae IgG titer, and other causes were diligently excluded based on patient history and laboratory and clinical data. On initial presentation, the patient was adequately treated for community-acquired pneumonia with atypical coverage with azithromycin. However, he continued to have active infection with positive M. pneumoniae IgM, which pointed towards macrolide resistance. Subsequently, he developed rhabdomyolysis followed by progressive weakness and numbness with neuropathy, which is an unusual and rare extrapulmonary manifestation of M. pneumoniae infection, and required treatment with intravenous hydration, high-dose prednisone, and IVIG.

Conclusions
Extrapulmonary manifestations of mycoplasma infection can cause significant morbidity and even be lifethreatening. This case highlights the need to maintain a high index of suspicion for rare extrapulmonary manifestations such as rhabdomyolysis and progressive neuropathy. The use of appropriate antibiotics against mycoplasma infection with consideration for macrolide resistance along with immunosuppressive or immunomodulatory therapy for severe extrapulmonary manifestations may lead to a better outcome as was evident in our case.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.